Method for the production of a dosage form

ABSTRACT

A method is described for producing a dosage form and granules including surface-reacted calcium carbonate. Also described, are tablets and/or capsules obtained by the method. Methods using such a surface-reacted calcium carbonate, and a dosage form comprising the granules are also described. Further, methods of using the granules, or the tablets and/or capsules, or the dosage form in a pharmaceutical product, a nutraceutical product, an agricultural product, a cosmetic product, a home product, a food product, a packaging product and a personal care product are also described. A pharmaceutical product, a nutraceutical product, an agricultural product, a cosmetic product, a home product, a food product, a packaging product and a personal care product including the granules, or the tablets and/or capsules, or the dosage form are also described.

The present invention relates to a method for producing a dosage form,granules consisting of surface reacted calcium carbonate, and tabletsand/or capsules obtained by the method, the use of a surface-reactedcalcium carbonate in a such a method, a dosage form comprising thegranules, the use of the granules, or the tablets and/or capsules, orthe dosage form in a pharmaceutical, nutraceutical, agriculturalcosmetic, home, food, packaging and personal care product as well as apharmaceutical, nutraceutical, agricultural, cosmetic, home, food,packaging and personal care product comprising the granules, or thetablets and/or capsules, or the dosage form.

Surface-reacted calcium carbonate powder can be used as a carrier in agreat variety of applications due to its high porosity and capacity ofloading active/inactive agents. Thus, surface-reacted calcium carbonateis gaining more and more importance in the production of dosage forms.Depending on the final use, the carrier material or matrix for suchdosage forms needs to be first mixed with the required active ingredientor inactive precursor material and compatible formulating aid(s) needsto be found in order to be able to produce the dosage form. Such dosageforms are mainly manufactured out of powders. However, a frequentproblem arising for such powders is that they are not free flowing, havelow bulk density and generate too much dust. Thus, methods have beendeveloped for producing dosage forms which are in form of a compactedmaterial comprising surface-reacted calcium carbonate and avoiding theforegoing disadvantages.

For examples, unpublished European patent application EP 15 160 194.5refers to a method for producing a dispersible dosage form, comprisingthe steps of: a) providing a functionalized calcium carbonate-comprisingmaterial, which is a reaction product of natural ground or precipitatedcalcium carbonate with carbon dioxide and one or more acids in anaqueous medium, wherein the carbon dioxide is formed in situ by the acidtreatment and/or is supplied from an external source, b) providing atleast one disintegrant; c) optionally providing at least one furtherformulating aid; d) mixing the functionalised calciumcarbonate-comprising material of step a), the at least one disintegrantof step b) and the optionally at least one further formulating aid ofstep c); and e) compacting the mixture obtained in step d) by means of aroller compactor at a compaction pressure in the range from 2 to 20 barinto a ribbon; and f) milling the ribbon of step e) into granules, g)sieving of the granules of step f) by at least one mesh size.

Unpublished European patent application EP 14 199 037.4 refers to amethod for producing a pharmaceutical delivery system, comprising thesteps of: a) providing surface-reacted calcium carbonate, which is areaction product of natural ground or precipitated calcium carbonatewith carbon dioxide and one or more acids in an aqueous medium, whereinthe carbon dioxide is formed in situ by the acid treatment and/or issupplied from an external source; b) providing at least onepharmaceutically active agent or pharmaceutically inactive precursorthereof; c) providing at least one formulating aid; d) mixing thesurface-reacted calcium carbonate of step a), the at least onepharmaceutically active agent or pharmaceutically inactive precursorthereof of step b) and the at least one formulating aid of step c); ande) compacting the mixture obtained in step d) by means of a rollercompacter at a compaction pressure in the range from 4 to 20 bar; and f)compacting the roller compacted mixture obtained in step e) forobtaining the pharmaceutical delivery system.

Unpublished European patent application EP 15 197 395.5 refers to amethod for the production of granules comprising surface-reacted calciumcarbonate, characterized by the steps of a) providing surface-reactedcalcium carbonate, wherein the surface-reacted calcium carbonate is areaction product of natural ground or precipitated calcium carbonatewith carbon dioxide and one or more H₃O⁺ ion donors in an aqueousmedium, wherein the carbon dioxide is formed in-situ by the H₃O⁺ iondonor treatment and/or is supplied from an external source; b) providingone or more active ingredient(s) in liquid form, c) saturating thesurface-reacted calcium carbonate with the one or more activeingredient(s) in liquid form, d) providing one or more binder, and e)combining the saturated surface-reacted calcium carbonate obtained instep c) with the one or more binder of step d) under agitation in anagitation device.

However, also the methods described in the foregoing documents requirethe use of formulating aid(s) such as binder(s) and/or disintegrant(s)during compacting which need(s) to be compatible with thesurface-reacted calcium carbonate powder as well as the active agentused, and further must be suitable for the desired end use, e.g. must beapproved for human and/or animal consumption.

Thus, there is a continuous need for dosage forms and methods for theirproduction which provide the same or even better performance thanexisting dosage forms and especially allows for producing a dosage formwhich is compacted in the absence of formulating aid(s) such asbinder(s) and/or disintegrant(s). Furthermore, it is desired that themethod allows for producing a dosage form having improved flowability,loose bulk- and tapped bulk-density, compared to the powder they havebeen made of, and are significantly less or almost non-dusting and thuscan be easily be used in the further processing. In addition thereto, itis desired to provide a method for producing the dosage form which isefficient and allows for sufficient compacting of the dosage form.

It is thus an object of the present invention to provide a method forproducing a dosage form. Another object may also be seen in theprovision of a highly efficient compacting method for producing a dosageform. A further object may be seen in the provision of a method forproducing a dosage form which is compacted in the absence of formulatingaid(s) such as binder(s) and/or disintegrant(s). Another object may beseen in the provision of a method for producing a dosage form havingimproved flowability, loose bulk- and tapped bulk-density, compared tothe powder they have been made of, and are significantly less or almostnon-dusting and thus can be easily be used in the further processing.

One or more of the foregoing and other problems are solved by thesubject-matter as defined herein in the independent claims. Advantageousembodiments of the present invention are defined in the correspondingsub-claims.

A first aspect of the present invention relates to a method forproducing a dosage form. The method comprising the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

According to another aspect of the present invention, granulesconsisting of surface reacted calcium carbonate as defined herein andoptionally mixed with at least one formulating aid as defined hereinand/or loaded with at least one active ingredient and/or inactiveprecursor thereof as defined herein are provided. According to a furtheraspect of the present invention, tablets and/or capsules obtained by themethod as defined herein are provided.

According to a still further aspect of the present invention, a dosageform, preferably a tablet, mini-tablet or capsule, comprising thegranules, as defined herein, is provided.

According to still another aspect of the present invention, the use ofthe granules as defined herein, or the tablets and/or capsules asdefined herein, or the dosage form as defined herein in apharmaceutical, nutraceutical, agricultural, cosmetic, home, food,packaging and personal care product is provided.

According to a further aspect of the present invention, apharmaceutical, nutraceutical, agricultural, cosmetic, home, food,packaging and personal care product comprising the granules as definedherein, or the tablets and/or capsules as defined herein, or the dosageform as defined herein, is provided.

According to another aspect of the present invention, the use of asurface-reacted calcium carbonate in a method as defined herein, isprovided.

According to one embodiment of the present method, the natural groundcalcium carbonate is selected from calcium carbonate containing mineralsselected from the group comprising marble, chalk, dolomite, limestoneand mixtures thereof; or the precipitated calcium carbonate is selectedfrom the group comprising precipitated calcium carbonates havingaragonitic, vateritic or calcitic mineralogical crystal forms andmixtures thereof.

According to another embodiment of the present method, thesurface-reacted calcium carbonate a) has a BET specific surface area offrom 20 m²/g to 450 m²/g, preferably from 20 m²/g to 250 m²/g, morepreferably from 30 m²/g to 160 m²/g, most preferably from 40 m²/g to 150m²/g, still more preferably from 40 m²/g to 140 m²/g measured using thenitrogen and BET method according to ISO 9277; and/or b) comprisesparticles having a volume median grain diameter d₅₀ of from 1 μm to 50μm, preferably from 1 to 45 μm, more preferably from 2 to 30 μm, evenmore preferably from 3 to 15 μm, and most preferably from 4 to 12 μm;and/or c) has an intra-particle intruded specific pore volume within therange of 0.15 to 1.35 cm³/g, preferably of 0.30 to 1.30 cm³/g, and mostpreferably of 0.40 to 1.25 cm³/g, calculated from a mercury intrusionporosimetry measurement.

According to yet another embodiment of the present method, rollercompacting step b) is carried out at a roller compaction pressure in therange from 1 to 28 kN/cm, more preferably in the range from 1 to 20kN/cm and most preferably in the range from 2 to 10 kN/cm.

According to one embodiment of the present method, the method furthercomprising a step d) of sieving the granules of step c) by at least onemesh size.

According to another embodiment of the present method, sieving step d)is carried out by sieving on two or more different mesh sizes,preferably with mesh sizes of 90 μm, 180 μm, 250 μm, 355 μm, 500 μm and710 μm.

According to yet another embodiment of the present method, the methodfurther comprising a step e1) of mixing the compacted form obtained instep b) or the granules obtained in step c) and/or, if present, step d)with at least one formulating aid.

According to one embodiment of the present method, the at least oneformulating aid is selected from the group comprising a disintegrant,preferably selected form the group comprising modified cellulose gums,insoluble cross-linked polyvinylpyrrolidones, starch glycolates, microcrystalline cellulose, pregelatinized starch, sodium carboxymethylstarch, low-substituted hydroxypropyl cellulose, homopolymers ofN-vinyl-2-pyrrolidone, alkyl-, hydroxyalkyl-, carboxyalkyl-celluloseesters, alginates, microcrystalline cellulose and its polymorphic forms,ion exchange resins, gums, chitin, chitosan, clays, gellan gum,crosslinked polacrillin copolymers, agar, gelatine, dextrines, acrylicacid polymers, carboxymethylcellulose sodium/calcium, hydroxpropylmethyl cellulose phthalate, shellac or mixtures thereof, lubricants,especially an inner-phase lubricant and/or an outer-phase lubricant,impact modifiers, plasticizers, waxes, stabilizers, pigments, coloringagents, scenting agents, taste masking agents, flavoring agents,sweeteners, mouth-feel improvers, diluents, film forming agents,adhesives, buffers, adsorbents, odour-masking agents and mixturesthereof.

According to another embodiment of the present method, the methodfurther comprising a step e2) of loading the compacted form obtained instep b) or the granules obtained in step c), if present, step d) with atleast one active ingredient and/or inactive precursor thereof forobtaining loaded granules.

According to yet another embodiment of the present method, the at leastone active ingredient and/or inactive precursor thereof is selected fromthe group comprising fragrances, flavours, herbal extracts, fruitextracts, nutrients, trace minerals, repellents, food, cosmetics, flameretardants, enzymes, macromolecules, pesticides, fertilizers, preservingagents, antioxidants, reactive chemicals, pharmaceutically active agentsor pharmaceutically inactive precursors of synthetic origin,semi-synthetic origin, natural origin thereof, and mixtures thereof.

According to one embodiment of the present method, the at least oneactive ingredient and/or inactive precursor thereof is in liquid form,preferably the at least one active ingredient and/or inactive precursorthereof is provided in a solvent, preferably the solvent is selectedfrom the group comprising water, methanol, ethanol, n-butanol,isopropanol, n-propanol, n-octanol, acetone, dimethylsulphoxide,dimethylformamide, tetrahydrofurane, vegetable oils and the derivativesthereof, animal oils and the derivatives thereof, molten fats and waxes,and mixtures thereof, and more preferably the solvent is water, ethanoland/or acetone.

According to another embodiment of the present method, loading step e2)is carried out by spraying or dropping the at least one activeingredient and/or inactive precursor thereof onto the compacted formobtained in step b) or the granules obtained in step c) or, if present,step d) and mixing it in a device selected from the group comprisingfluidized bed dryers/granulators, ploughshare mixer, vertical orhorizontal mixers, high or low shear mixer and high speed blenders.

According to yet another embodiment of the present method, the methodfurther comprising a final step f) of tableting the loaded granulesobtained in step e2) or filling the loaded granules obtained in step e2)into capsules.

It should be understood that for the purpose of the present inventionthe following terms have the following meaning.

For the purpose of the present invention, an “acid” is defined asBrønsted-Lowry acid, that is to say, it is an H₃O⁺ ion provider. An“acid salt” is defined as an H₃O⁺ ion-provider, e.g., ahydrogen-containing salt, which is partially neutralised by anelectropositive element. A “salt” is defined as an electrically neutralionic compound formed from anions and cations. A “partially crystallinesalt” is defined as a salt that, on XRD analysis, presents anessentially discrete diffraction pattern.

In accordance with the present invention, pK_(a) is the symbolrepresenting the acid dissociation constant associated with a givenionisable hydrogen in a given acid, and is indicative of the naturaldegree of dissociation of this hydrogen from this acid at equilibrium inwater at a given temperature. Such pK_(a) values may be found inreference textbooks such as Harris, D. C. “Quantitative ChemicalAnalysis: 3^(rd) Edition”, 1991, W.H. Freeman & Co. (USA), ISBN0-7167-2170-8.

A “surface-reacted calcium carbonate” is a material comprising calciumcarbonate and a water insoluble, at least partially crystalline,non-carbonate calcium salt, preferably, extending from the surface of atleast part of the calcium carbonate. The calcium ions forming said atleast partially crystalline non-carbonate calcium salt originate largelyfrom the starting calcium carbonate material that also serves to formthe surface-reacted calcium carbonate core. Such salts may include OH⁻anions and/or crystal water.

In the meaning of the present invention “water-insoluble” materials aredefined as materials which, when mixed with deionised water and filteredon a filter having a 0.2 μm pore size at 20° C. to recover the liquidfiltrate, provide less than or equal to 0.1 g of recovered solidmaterial following evaporation at 95 to 100° C. of 100 g of said liquidfiltrate. “Water-soluble” materials are defined as materials leading tothe recovery of greater than 0.1 g of recovered solid material followingevaporation at 95 to 100° C. of 100 g of said liquid filtrate.

A “specific surface area (SSA)” of a calcium carbonate in the meaning ofthe present invention is defined as the surface area of the calciumcarbonate divided by its mass. As used herein, the specific surface areais measured by nitrogen gas adsorption using the BET isotherm (ISO9277:2010) and is specified in m²/g.

It is appreciated that the term “at least one active ingredient and/orinactive precursor thereof” differs from formulating aid(s), i.e. the atleast one active ingredient and/or inactive precursor thereof does notinclude, nor are they by themselves, binders, disintegrants, lubricants,impact modifiers, plasticizers, waxes, stabilizers, pigments, coloringagents, scenting agents, taste masking agents, flavoring agents,mouth-feel improvers, diluents, film forming agents, adhesives, buffers,adsorbents, odour-masking agents and mixtures thereof.

The term “compacting” in the meaning of the present invention means areduction in volume and/or density and an increase of the granulehardness which is obtained under pressure.

Where the term “comprising” is used in the present description andclaims, it does not exclude other elements. For the purposes of thepresent invention, the term “consisting of” is considered to be apreferred embodiment of the term “comprising of”. If hereinafter a groupis defined to comprise at least a certain number of embodiments, this isalso to be understood to disclose a group, which preferably consistsonly of these embodiments.

Where an indefinite or definite article is used when referring to asingular noun, e.g. “a”, “an” or “the”, this includes a plural of thatnoun unless something else is specifically stated.

Terms like “obtainable” or “definable” and “obtained” or “defined” areused interchangeably. This e.g. means that, unless the context clearlydictates otherwise, the term “obtained” does not mean to indicate thate.g. an embodiment must be obtained by e.g. the sequence of stepsfollowing the term “obtained” though such a limited understanding isalways included by the terms “obtained” or “defined” as a preferredembodiment.

According to the present invention it has been found that a dosage formcan be prepared by compacting surface-reacted calcium carbonate in theabsence of formulating aids such as binders and/or disintegrants. Thecompacted surface-reacted calcium carbonate can then be loaded with atleast one active ingredient and/or inactive precursor thereof.Furthermore, the dosage form produced has improved flowability, loosebulk- and tapped bulk-density, compared to the powder it is made of, andis significantly less or almost non-dusting and thus can be easily beused in the further processing. In addition thereto, the method providesthe possibility of efficiently compacting the dosage form.

In the following, it is referred to further details of the presentinvention and especially the foregoing steps of the method for producinga dosage form.

Method Step a)

In step a) of the method of the present invention, surface-reactedcalcium carbonate is provided.

The surface-reacted calcium carbonate is a reaction product of naturalground calcium carbonate or precipitated calcium carbonate with carbondioxide and one or more H₃O⁺ ion donors, wherein the carbon dioxide isformed in-situ by the H₃O⁺ ion donors treatment and/or is supplied froman external source.

A H₃O⁺ ion donor in the context of the present invention is a Brønstedacid and/or an acid salt.

An “acid salt” is defined as an H₃O⁺ ion-provider, e.g., ahydrogen-containing salt, which is partially neutralised by anelectropositive element. A “salt” is defined as an electrically neutralionic compound formed from anions and cations. A “partially crystallinesalt” is defined as a salt that, on XRD analysis, presents anessentially discrete diffraction pattern.

In a preferred embodiment of the invention the surface-reacted calciumcarbonate is obtained by a process comprising the steps of: (a)providing a suspension of natural or precipitated calcium carbonate, (b)adding at least one acid having a pK_(a) value of 0 or less at 20° C. orhaving a pK_(a) value from 0 to 2.5 at 20° C. to the suspension of stepa), and (c) treating the suspension of step (a) with carbon dioxidebefore, during or after step (b). According to another embodiment thesurface-reacted calcium carbonate is obtained by a process comprisingthe steps of: (A) providing a natural or precipitated calcium carbonate,(B) providing at least one water-soluble acid, (C) providing gaseousCO₂, (D) contacting said natural or precipitated calcium carbonate ofstep (A) with the at least one acid of step (B) and with the CO₂ of step(C), characterised in that: (i) the at least one acid of step B) has apK_(a) of greater than 2.5 and less than or equal to 7 at 20° C.,associated with the ionisation of its first available hydrogen, and acorresponding anion is formed on loss of this first available hydrogencapable of forming a water-soluble calcium salt, and (ii) followingcontacting the at least one acid with natural or precipitated calciumcarbonate, at least one water-soluble salt, which in the case of ahydrogen-containing salt has a pK_(a) of greater than 7 at 20° C.,associated with the ionisation of the first available hydrogen, and thesalt anion of which is capable of forming water-insoluble calcium salts,is additionally provided.

“Natural ground calcium carbonate” (GCC) (or “natural calciumcarbonate”) preferably is selected from calcium carbonate containingminerals selected from the group comprising marble, chalk, dolomite,limestone and mixtures thereof. Natural ground calcium carbonate maycomprise further naturally occurring components such as magnesiumcarbonate, alumino silicate etc.

In general, the grinding of natural ground calcium carbonate may be adry or wet grinding step and may be carried out with any conventionalgrinding device, for example, under conditions such that comminutionpredominantly results from impacts with a secondary body, i.e. in one ormore of: a ball mill, a rod mill, a vibrating mill, a roll crusher, acentrifugal impact mill, a vertical bead mill, an attrition mill, a pinmill, a hammer mill, a pulveriser, a shredder, a de-clumper, a knifecutter, or other such equipment known to the skilled man. In case thecalcium carbonate containing mineral material comprises a wet groundcalcium carbonate containing mineral material, the grinding step may beperformed under conditions such that autogenous grinding takes placeand/or by horizontal ball milling, and/or other such processes known tothe skilled man. The wet processed natural ground calcium carbonatecontaining mineral material thus obtained may be washed and dewatered bywell-known processes, e.g. by flocculation, filtration or forcedevaporation prior to drying. The subsequent step of drying (ifnecessary) may be carried out in a single step such as spray drying, orin at least two steps. It is also common that such a mineral materialundergoes a beneficiation step (such as a flotation, bleaching ormagnetic separation step) to remove impurities.

“Precipitated calcium carbonate” (PCC) in the meaning of the presentinvention is a synthesized material, generally obtained by precipitationfollowing reaction of carbon dioxide and calcium hydroxide in an aqueousenvironment or by precipitation of calcium and carbonate ions, forexample CaCl₂) and Na₂CO₃, out of solution. Further possible ways ofproducing PCC are the lime soda process, or the Solvay process in whichPCC is a by-product of ammonia production. Precipitated calciumcarbonate exists in three primary crystalline forms: calcite, aragoniteand vaterite, and there are many different polymorphs (crystal habits)for each of these crystalline forms. Calcite has a trigonal structurewith typical crystal habits such as scalenohedral (S-PCC), rhombohedral(R-PCC), hexagonal prismatic, pinacoidal, colloidal (C-PCC), cubic, andprismatic (P-PCC). Aragonite is an orthorhombic structure with typicalcrystal habits of twinned hexagonal prismatic crystals, as well as adiverse assortment of thin elongated prismatic, curved bladed, steeppyramidal, chisel shaped crystals, branching tree, and coral orworm-like form. Vaterite belongs to the hexagonal crystal system. Theobtained PCC slurry can be mechanically dewatered and dried.

According to one embodiment of the present invention, the precipitatedcalcium carbonate is precipitated calcium carbonate, preferablycomprising aragonitic, vateritic or calcitic mineralogical crystal formsor mixtures thereof.

Precipitated calcium carbonate may be ground prior to the treatment withcarbon dioxide and at least one H₃O⁺ ion donor by the same means as usedfor grinding natural calcium carbonate as described above.

According to one embodiment of the present invention, the natural groundor precipitated calcium carbonate is in form of particles having aweight median particle size d₅₀ of 0.05 to 10.0 μm, preferably 0.2 to5.0 μm, more preferably 0.4 to 3.0 μm, most preferably 0.6 to 1.2 μm,especially 0.7 μm. According to a further embodiment of the presentinvention, the natural ground or precipitated calcium carbonate is inform of particles having a top cut particle size d₉₈ of 0.15 to 55 μm,preferably 1 to 40 μm, more preferably 2 to 25 μm, most preferably 3 to15 μm, especially 4 μm.

The natural ground and/or precipitated calcium carbonate may be used dryor suspended in water. Preferably, a corresponding slurry has a contentof natural ground or precipitated calcium carbonate within the range of1 wt.-% to 90 wt.-%, more preferably 3 wt.-% to 60 wt.-%, even morepreferably 5 wt.-% to 40 wt.-%, and most preferably 10 wt.-% to 25 wt.-%based on the weight of the slurry.

The one or more H₃O⁺ ion donor used for the preparation of surfacereacted calcium carbonate may be any strong acid, medium-strong acid, orweak acid, or mixtures thereof, generating H₃O⁺ ions under thepreparation conditions. According to the present invention, the at leastone H₃O⁺ ion donor can also be an acidic salt, generating H₃O⁺ ionsunder the preparation conditions.

According to one embodiment, the at least one H₃O⁺ ion donor is a strongacid having a pK_(a) of 0 or less at 20° C.

According to another embodiment, the at least one H₃O⁺ ion donor is amedium-strong acid having a pK_(a) value from 0 to 2.5 at 20° C. If thepK_(a) at 20° C. is 0 or less, the acid is preferably selected fromsulphuric acid, hydrochloric acid, or mixtures thereof. If the pK_(a) at20° C. is from 0 to 2.5, the H₃O⁺ ion donor is preferably selected fromH₂SO₃, H₃PO₄, oxalic acid, or mixtures thereof. The at least one H₃O⁺ion donor can also be an acidic salt, for example, HSO₄ ⁻ or H₂PO₄ ⁻,being at least partially neutralized by a corresponding cation such asLi⁺, Na⁺ or K⁺, or HPO₄ ²⁻, being at least partially neutralised by acorresponding cation such as Li⁺, Na⁺, K⁺, Mg²⁺ or Ca²⁺. The at leastone H₃O⁺ ion donor can also be a mixture of one or more acids and one ormore acidic salts.

According to still another embodiment, the at least one H₃O⁺ ion donoris a weak acid having a pK_(a) value of greater than 2.5 and less thanor equal to 7, when measured at 20° C., associated with the ionisationof the first available hydrogen, and having a corresponding anion, whichis capable of forming water-soluble calcium salts. Subsequently, atleast one water-soluble salt, which in the case of a hydrogen-containingsalt has a pK_(a) of greater than 7, when measured at 20° C., associatedwith the ionisation of the first available hydrogen, and the salt anionof which is capable of forming water-insoluble calcium salts, isadditionally provided. According to the preferred embodiment, the weakacid has a pK_(a) value from greater than 2.5 to 5 at 20° C., and morepreferably the weak acid is selected from the group consisting of aceticacid, formic acid, propanoic acid, and mixtures thereof. Exemplarycations of said water-soluble salt are selected from the groupconsisting of potassium, sodium, lithium and mixtures thereof. In a morepreferred embodiment, said cation is sodium or potassium. Exemplaryanions of said water-soluble salt are selected from the group consistingof phosphate, dihydrogen phosphate, monohydrogen phosphate, oxalate,silicate, mixtures thereof and hydrates thereof. In a more preferredembodiment, said anion is selected from the group consisting ofphosphate, dihydrogen phosphate, monohydrogen phosphate, mixturesthereof and hydrates thereof. In a most preferred embodiment, said anionis selected from the group consisting of dihydrogen phosphate,monohydrogen phosphate, mixtures thereof and hydrates thereof.Water-soluble salt addition may be performed dropwise or in one step. Inthe case of drop wise addition, this addition preferably takes placewithin a time period of 10 minutes. It is more preferred to add saidsalt in one step.

According to one embodiment of the present invention, the at least oneH₃O⁺ ion donor is selected from the group consisting of hydrochloricacid, sulphuric acid, sulphurous acid, phosphoric acid, citric acid,oxalic acid, acetic acid, formic acid, and mixtures thereof. Preferablythe at least one H₃O⁺ ion donor is selected from the group consisting ofhydrochloric acid, sulphuric acid, sulphurous acid, phosphoric acid,oxalic acid, H₂PO₄, being at least partially neutralised by acorresponding cation such as Li⁺, Na⁺ or K⁺, HPO₄ ²⁻, being at leastpartially neutralised by a corresponding cation such as Li⁺, Na⁺, K⁺,Mg⁺, or Ca⁺ and mixtures thereof, more preferably the at least one acidis selected from the group consisting of hydrochloric acid, sulphuricacid, sulphurous acid, phosphoric acid, oxalic acid, or mixturesthereof, and most preferably, the at least one H₃O⁺ ion donor isphosphoric acid.

The one or more H₃O⁺ ion donor can be added to the suspension as aconcentrated solution or a more diluted solution. Preferably, the molarratio of the H₃O⁺ ion donor to the natural or precipitated calciumcarbonate is from 0.01 to 4, more preferably from 0.02 to 2, even morepreferably 0.05 to 1 and most preferably 0.1 to 0.58.

As an alternative, it is also possible to add the H₃O⁺ ion donor to thewater before the natural ground or precipitated calcium carbonate issuspended.

In a next step, the natural ground or precipitated calcium carbonate istreated with carbon dioxide. If a strong acid such as sulphuric acid orhydrochloric acid is used for the H₃O⁺ ion donor treatment of thenatural ground or precipitated calcium carbonate, the carbon dioxide isautomatically formed. Alternatively or additionally, the carbon dioxidecan be supplied from an external source.

H₃O⁺ ion donor treatment and treatment with carbon dioxide can becarried out simultaneously which is the case when a strong ormedium-strong acid is used. It is also possible to carry out H₃O⁺ iondonor treatment first, e.g. with a medium strong acid having a pK_(a) inthe range of 0 to 2.5 at 20° C., wherein carbon dioxide is formedin-situ, and thus, the carbon dioxide treatment will automatically becarried out simultaneously with the H₃O⁺ ion donor treatment, followedby the additional treatment with carbon dioxide supplied from anexternal source.

Preferably, the concentration of gaseous carbon dioxide in thesuspension is, in terms of volume, such that the ratio (volume ofsuspension):(volume of gaseous CO₂) is from 1:0.05 to 1:20, even morepreferably 1:0.05 to 1:5.

In a preferred embodiment, the H₃O⁺ ion donor treatment step and/or thecarbon dioxide treatment step are repeated at least once, morepreferably several times. According to one embodiment, the at least oneH₃O⁺ ion donor is added over a time period of at least about 5 min,preferably at least about 10 min, typically from about 10 to about 20min, more preferably about 30 min, even more preferably about 45 min,and sometimes about 1 h or more.

Subsequent to the H₃O⁺ ion donor treatment and carbon dioxide treatment,the pH of the aqueous suspension, measured at 20° C., naturally reachesa value of greater than 6.0, preferably greater than 6.5, morepreferably greater than 7.0, even more preferably greater than 7.5,thereby preparing the surface-reacted natural or precipitated calciumcarbonate as an aqueous suspension having a pH of greater than 6.0,preferably greater than 6.5, more preferably greater than 7.0, even morepreferably greater than 7.5.

Further details about the preparation of the surface-reacted naturalground calcium carbonate are disclosed in WO 00/39222 A1, WO 2004/083316A1, WO 2005/121257 A2, WO 2009/074492 A1, EP 2 264 108 A1, EP 2 264 109A1 and US 2004/0020410 A1, the content of these references herewithbeing included in the present application.

Similarly, surface-reacted precipitated calcium carbonate is obtained.As can be taken in detail from WO 2009/074492 A1, surface-reactedprecipitated calcium carbonate is obtained by contacting precipitatedcalcium carbonate with H₃O⁺ ions and with anions being solubilized in anaqueous medium and being capable of forming water-insoluble calciumsalts, in an aqueous medium to form a slurry of surface-reactedprecipitated calcium carbonate, wherein said surface-reactedprecipitated calcium carbonate comprises an insoluble, at leastpartially crystalline calcium salt of said anion formed on the surfaceof at least part of the precipitated calcium carbonate.

Said solubilized calcium ions correspond to an excess of solubilizedcalcium ions relative to the solubilized calcium ions naturallygenerated on dissolution of precipitated calcium carbonate by H₃O⁺ ions,where said H₃O⁺ ions are provided solely in the form of a counterion tothe anion, i.e. via the addition of the anion in the form of an acid ornon-calcium acid salt, and in absence of any further calcium ion orcalcium ion generating source.

Said excess solubilized calcium ions are preferably provided by theaddition of a soluble neutral or acid calcium salt, or by the additionof an acid or a neutral or acid non-calcium salt which generates asoluble neutral or acid calcium salt in-situ.

Said H₃O⁺ ions may be provided by the addition of an acid or an acidsalt of said anion, or the addition of an acid or an acid salt whichsimultaneously serves to provide all or part of said excess solubilizedcalcium ions.

In a further preferred embodiment of the preparation of thesurface-reacted natural ground or precipitated calcium carbonate, thenatural ground or precipitated calcium carbonate is reacted with theacid and/or the carbon dioxide in the presence of at least one compoundselected from the group consisting of silicate, silica, aluminiumhydroxide, earth alkali aluminate such as sodium or potassium aluminate,magnesium oxide, or mixtures thereof. Preferably, the at least onesilicate is selected from an aluminium silicate, a calcium silicate, oran earth alkali metal silicate. These components can be added to anaqueous suspension comprising the natural or precipitated calciumcarbonate before adding the acid and/or carbon dioxide.

Alternatively, the silicate and/or silica and/or aluminium hydroxideand/or earth alkali aluminate and/or magnesium oxide component(s) can beadded to the aqueous suspension of natural or precipitated calciumcarbonate while the reaction of natural ground or precipitated calciumcarbonate with an acid and carbon dioxide has already started. Furtherdetails about the preparation of the surface-reacted natural ground orprecipitated calcium carbonate in the presence of at least one silicateand/or silica and/or aluminium hydroxide and/or earth alkali aluminatecomponent(s) are disclosed in WO 2004/083316 A1, the content of thisreference herewith being included in the present application.

The surface-reacted calcium carbonate can be kept in suspension,optionally further stabilised by a dispersant. Conventional dispersantsknown to the skilled person can be used. A preferred dispersant iscomprised of polyacrylic acids and/or carboxymethylcelluloses.

Alternatively, the aqueous suspension described above can be dried,thereby obtaining the solid (i.e. dry or containing as little water thatit is not in a fluid form) surface-reacted natural or precipitatedcalcium carbonate in the form of granules or a powder.

The surface reacted calcium carbonate may have different particleshapes, such as e.g. the shape of roses, golf balls and/or brains.

In a preferred embodiment, the surface-reacted calcium carbonate has aspecific surface area of from 20 m²/g to 450 m²/g, preferably from 20m²/g to 250 m²/g, more preferably from 30 m²/g to 160 m²/g, mostpreferably from 40 m²/g to 150 m²/g, still more preferably from 40 m²/gto 140 m²/g measured using the nitrogen and BET method according to ISO9277. The BET specific surface area in the meaning of the presentinvention is defined as the surface area of the particles divided by themass of the particles. As used therein the specific surface area ismeasured by adsorption using the BET isotherm (ISO 9277:2010) and isspecified in m²/g.

According to one embodiment, the surface-reacted calcium carbonatecomprises particles having a volume median grain diameter d₅₀ (vol) offrom 1 to 50 μm, preferably from 1 to 45 μm, more preferably from 2 to30 μm, even more preferably from 3 to 15 μm, and most preferably from 4to 12 μm.

It may furthermore be preferred that the surface-reacted calciumcarbonate comprises particles having a grain diameter d₉₈ (vol) of lessthan or equal to 40.0 μm. preferably less than or equal to 30.0 μm, morepreferably less than or equal to 25.0 μm, still more preferably of lessthan or equal to 20.0 μm, more preferably of less than or equal to 19.0μm. Preferably, the surface-reacted calcium carbonate comprisesparticles having a grain diameter d₉₈ (vol) in the range of from 5.0 to40 μm, preferably form 6 to 30 μm, more preferably form 7.0 to 25.0 μm,still more preferably of from 10.0 to 20.0 μm, more preferably of from11.0 to 19.0 μm.

The value d_(x) represents the diameter relative to which x % of theparticles have diameters less than d_(x). This means that the d₉₈ valueis the particle size at which 98% of all particles are smaller. The d₉₈value is also designated as “top cut”. The d_(x) values may be given involume or weight percent. The d₅₀ (wt) value is thus the weight medianparticle size, i.e. 50 wt.-% of all grains are smaller than thisparticle size, and the d₅₀ (vol) value is the volume median particlesize, i.e. 50 vol. % of all grains are smaller than this particle size.

Volume median grain diameter d₅₀ was evaluated using a MalvernMastersizer 2000 Laser Diffraction System. The d₅₀ or d₉₈ value,measured using a Malvern Mastersizer 2000 Laser Diffraction System,indicates a diameter value such that 50% or 98% by volume, respectively,of the particles have a diameter of less than this value. The raw dataobtained by the measurement are analysed using the Mie theory, with aparticle refractive index of 1.57 and an absorption index of 0.005.

The weight median grain diameter is determined by the sedimentationmethod, which is an analysis of sedimentation behaviour in a gravimetricfield. The measurement is made with a Sedigraph™ 5100 or 5120,Micromeritics Instrument Corporation. The method and the instrument areknown to the skilled person and are commonly used to determine grainsize of fillers and pigments. The measurement is carried out in anaqueous solution of 0.1 wt.-% Na₄P₂O₇. The samples were dispersed usinga high speed stirrer and sonicated.

The processes and instruments are known to the skilled person and arecommonly used to determine grain size of fillers and pigments.

The specific pore volume is measured using a mercury intrusionporosimetry measurement using a Micromeritics Autopore V 9620 mercuryporosimeter having a maximum applied pressure of mercury 414 MPa (60 000psi), equivalent to a Laplace throat diameter of 0.004 μm (˜nm). Theequilibration time used at each pressure step is 20 seconds. The samplematerial is sealed in a 5 cm³ chamber powder penetrometer for analysis.The data are corrected for mercury compression, penetrometer expansionand sample material compression using the software Pore-Comp (Gane, P.A. C., Kettle, J. P., Matthews, G. P. and Ridgway, C. J., “Void SpaceStructure of Compressible Polymer Spheres and Consolidated CalciumCarbonate Paper-Coating Formulations”, Industrial and EngineeringChemistry Research, 35(5), 1996, p 1753-1764).

The total pore volume seen in the cumulative intrusion data can beseparated into two regions with the intrusion data from 214 μm down toabout 1-4 μm showing the coarse packing of the sample between anyagglomerate structures contributing strongly. Below these diameters liesthe fine interparticle packing of the particles themselves. If they alsohave intraparticle pores, then this region appears bi modal, and bytaking the specific pore volume intruded by mercury into pores finerthan the modal turning point, i.e. finer than the bi-modal point ofinflection, we thus define the specific intraparticle pore volume. Thesum of these three regions gives the total overall pore volume of thepowder, but depends strongly on the original sample compaction/settlingof the powder at the coarse pore end of the distribution.

By taking the first derivative of the cumulative intrusion curve thepore size distributions based on equivalent Laplace diameter, inevitablyincluding pore-shielding, are revealed. The differential curves clearlyshow the coarse agglomerate pore structure region, the interparticlepore region and the intraparticle pore region, if present. Knowing theintraparticle pore diameter range it is possible to subtract theremainder interparticle and interagglomerate pore volume from the totalpore volume to deliver the desired pore volume of the internal poresalone in terms of the pore volume per unit mass (specific pore volume).The same principle of subtraction, of course, applies for isolating anyof the other pore size regions of interest.

Preferably, the surface-reacted calcium carbonate has an intra-particleintruded specific pore volume in the range from 0.15 to 1.35 cm³/g,preferably of 0.30 to 1.30 cm³/g, and most preferably of 0.40 to 1.25cm³/g, calculated from mercury intrusion porosimetry measurement.

The pore diameter of the surface-reacted calcium carbonate preferably isin a range of from 4 to 500 nm, more preferably in a range of between 20and 80 nm, especially from 30 to 70 nm, e.g. 50 nm determined by mercuryporosimetry measurement.

The intra-particle pore size of the surface-reacted calcium carbonatepreferably is in a range of from 0.004 to 1.6 μm, more preferably in arange of between 0.005 to 1.3 μm, especially preferably from 0.006 to1.15 μm and most preferably of 0.007 to 1.0 μm, e.g. 0.004 to 0.51 μmdetermined by mercury porosimetry measurement.

According to a preferred embodiment the intra- and/or inter particlepores of the surface-reacted calcium carbonate provided in step a) arehollow and, therefore, the surface-reacted calcium carbonate of step a)is unloaded.

The surface-reacted calcium carbonate may be in the form of dust orpowder and preferably in the form of powder.

Method Step b)

According to step b) of the instant method, the surface-reacted calciumcarbonate of step a) is compacted by means of a roller compacter at acompaction pressure in the range from 1 to 30 kN/cm into a compactedform.

The term “roller compacting” refers to a process in which fine powdersare forced between two counter rotating rolls and pressed into acompacted form such as a ribbon, needles and/or flakes.

For the purposes of the present invention, roller compacting can becarried out with any suitable roller compactor known to the skilledperson. For example, roller compacting is carried out with aFitzpatrick® Chilsonator CCS220 roller compactor of the FitzpatrickCompany, USA.

It is one requirement of the instant method that method step b) iscarried out at a compaction pressure in the range from 1 to 30 kN/cm.Preferably, roller compacting step b) is carried out at a rollercompaction pressure in the range from 1 to 28 kN/cm, more preferably inthe range from 1 to 20 kN/cm and most preferably in the range from 2 to10 kN/cm.

Additionally or alternatively, the feed rate and/or the roll speedduring roller compacting step is/are adjusted such that a thickness offrom 0.2 to 6 mm, preferably from 0.3 to 3 mm and more preferably from0.4 to 1 mm for the compacted form is obtained. For example, the feedrate or the roll speed during roller compacting step d) is adjusted suchthat a thickness of from 0.2 to 6 mm, preferably from 0.3 to 3 mm andmore preferably from 0.4 to 1 mm for the compacted form is obtained.Alternatively, the feed rate and the roll speed during roller compactingstep d) are adjusted such that a thickness of from 0.2 to 6 mm,preferably from 0.3 to 3 mm and more preferably from 0.4 to 1 mm for thecompacted form is obtained.

It is one advantage of the present method that the compacting of thesurface-reacted calcium carbonate can be carried out in the absence offormulating aid(s) such as binder(s) and/or disintegrant(s).

Therefore, one specific requirement of the present invention is that thecompacted form of the surface-reacted calcium carbonate obtained in stepb) consists of the surface-reacted calcium carbonate of step a).

Method Step c)

According to step c) of the instant method, the compacted form obtainedin step b) is milled into granules.

Milling is carried out with any conventional mill known to the skilledperson. For example, milling is carried out with a FitzMill® from theFitzpatrick Company, USA.

In one embodiment, the obtained granules of step c) have a median grainsize of from 10 to 4 500 μm, preferably from 50 to 2 500 μm and morepreferably from 100 to 1 200 μm; and still more preferably 180 to 710μm.

Additionally or alternatively, the obtained granules of step c) have aBET specific surface area of from 20 m²/g to 450 m²/g, preferably from20 m²/g to 250 m²/g, more preferably from 30 m²/g to 160 m²/g, mostpreferably from 40 m²/g to 150 m²/g, still more preferably from 40 m²/gto 140 m²/g measured using the nitrogen and BET method according to ISO9277.

Additionally or alternatively, the obtained granules of step c) have abulk density of from 0.1 to 0.9 g/mL, preferably from 0.2 to 0.8 g/mL,more preferably from 0.3 to 0.7 g/mL, most preferably from 0.4 to 0.6g/mL.

Additionally or alternatively, the obtained granules of step c) have atapped density of from 0.1 to 0.9 g/mL, preferably from 0.2 to 0.9 g/mL,more preferably from 0.3 to 0.8 g/mL, most preferably from 0.4 to 0.7g/mL, still more preferably from 0.5 to 0.7 g/mL.

Additionally or alternatively, the obtained granules of step c) have acompressibility index of from 10 to 40, preferably from 12 to 35, morepreferably from 14 to 32, most preferably from 14 to 30, still morepreferably from 15 to 28.

Additionally or alternatively, the obtained granules of step c) have anangle of repose of from 10 to 80°, preferably from 15 to 75°, morepreferably from 20 to 70°, most preferably from 30 to 65°, still morepreferably from 35 to 60°.

Preferably, the obtained granules of step c) have

-   -   i) a median grain size of from 10 to 4 500 μm, preferably from        50 to 2 500 μm and more preferably from 100 to 1 200 μm; and        still more preferably 180 to 710 μm; and    -   ii) a BET specific surface area of from 20 m²/g to 450 m²/g,        preferably from 20 m²/g to 250 m²/g, more preferably from 30        m²/g to 160 m²/g, most preferably from 40 m²/g to 150 m²/g,        still more preferably from 40 m²/g to 140 m²/g measured using        the nitrogen and BET method according to ISO 9277; and    -   iii) a bulk density of from 0.1 to 0.9 g/mL, preferably from 0.2        to 0.8 g/mL, more preferably from 0.3 to 0.7 g/mL, most        preferably from 0.4 to 0.6 g/mL; and iv) a tapped density of        from 0.1 to 0.9 g/mL, preferably from 0.2 to 0.9 g/mL, more        preferably from 0.3 to 0.8 g/mL, most preferably from 0.4 to 0.7        g/mL, still more preferably from 0.5 to 0.7 g/mL; and    -   v) a compressibility index of from 10 to 40, preferably from 12        to 35, more preferably from 14 to 32, most preferably from 14 to        30, still more preferably from 15 to 28; and    -   vi) an angle of repose of from 10 to 80°, preferably from 15 to        75°, more preferably from 20 to 70°, most preferably from 30 to        65°, still more preferably from 35 to 60°.

Optional Method Steps

According to optional method step d) of the present invention, thegranules obtained in step c) are submitted to at least on sieving stepd) by at least one mesh size.

Such sieving can be carried out with any conventional sieving meansknown to the skilled person. The sieving can be carried out using one ormore mesh sizes. Suitable mesh sizes are, but not limited to mesh sizesin the order of 90 μm, 180 μm, 250 μm, 355 μm, 500 μm and 710 μm.

The sieved granules, thus have a median grain size of from 180 to 710 μmobtained by sieving on different mesh sizes, preferably by sieving withmesh sizes in the order of 90 μm, 180 μm, 250 μm, 355 μm, 500 μm and 710μm. More preferably, by sieving with mesh sizes in the order of 90 μm,180 μm, 250 μm, 355 μm, 500 μm and 710 μm and combining the sievedgranules such that granules having median grain sizes of less than 90 μmand more than 710 μm are excluded. For example, sieving is carried outwith a Vibrating sieve tower of Vibro Retsch, Switzerland.

In one embodiment, the sieving is carried out using mesh sizes in theorder of 180 μm, 250 μm, 355 μm, 500 μm and 710 μm.

The sieved granules, thus have a median grain size of from 180 to 710 μmobtained by sieving on different mesh sizes, preferably by sieving withmesh sizes in the order of 180 μm, 250 μm, 355 μm, 500 μm and 710 μm.More preferably, by sieving with mesh sizes in the order of 180 μm, 250μm, 355 μm, 500 μm and 710 μm and combining the sieved granules suchthat granules having median grain sizes of less than 180 μm and morethan 710 μm are excluded. For example, sieving is carried out with aVibrating sieve tower of Vibro Retsch, Switzerland.

In an alternative embodiment, the sieving is carried out using meshsizes in the order of 250 μm, 355 μm, 500 μm and 710 μm.

The sieved granules thus have a median grain size of from 250 to 710 μmobtained by sieving on different mesh sizes, preferably by sieving withmesh sizes in the order of 250 μm, 355 μm, 500 μm and 710 μm. Morepreferably, by sieving with mesh sizes in the order of 250 μm, 355 μm,500 μm and 710 μm and combining the sieved granules such that granuleshaving median grain sizes of less than 250 μm and more than 710 μm areexcluded. For example, sieving is carried out with a Vibrating sievetower of Vibro Retsch, Switzerland.

It lies within the understanding of the present invention that othermesh sizes and combination of other mesh sizes lie within the spirit ofthe present invention.

In this embodiment, the method for producing a dosage form comprises,preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules; and    -   d) sieving of the granules of step c) by at least one mesh size;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

As already outlined above, the compacted form of the surface-reactedcalcium carbonate obtained in step c) is prepared in the absence offormulating aid(s) such as binder(s) and/or disintegrant(s).

However, the compacted form of the surface-reacted calcium carbonateobtained in step b) can be mixed with at least one formulating aid.

Thus, in one embodiment, the method further comprises a step e1) ofmixing the granules obtained in step c) and/or, if present, step d) withat least one formulating aid. Preferably, the granules obtained in stepd) are mixed with the at least one formulating aid in a mixing step e1).

Mixing step e1) can be carried out by mixing the granules obtained instep c) and/or, if present, step d) with the at least one formulatingaid in any order to form a mixture.

For the purposes of the present invention, any suitable mixing meansknown in the art may be used for carrying out mixing step e1). However,mixing step e1) preferably takes place in a mixer and/or blender,preferably a mixer such as a tumbling mixer.

The expression “at least one” formulating aid means that the formulatingaid comprises one or more formulating aid(s).

According to one embodiment of the present invention, the formulatingaid comprises only one formulating aid. According to another embodimentof the present invention, the formulating aid comprises a mixture of twoor more formulating aids. For example, the formulating aid comprises amixture of two or three formulating aids.

In one embodiment, the at least one formulating aid comprises only oneformulating aid.

For example, the at least one formulating aid is selected from the groupcomprising disintegrants, lubricants, impact modifiers, plasticizers,waxes, stabilizers, pigments, coloring agents, scenting agents, tastemasking agents, flavoring agents, sweeteners, mouth-feel improvers,diluents, film forming agents, adhesives, buffers, adsorbents,odour-masking agents and mixtures thereof. In one embodiment, the atleast one formulating aid may be also a binder.

It lies within the understanding of the skilled person that thementioned formulating aid(s) are of mere illustrative character and arenot intended to be of limiting character.

Preferably, the at least one formulating aid is a disintegrant selectedform the group comprising modified cellulose gums, insolublecross-linked polyvinylpyrrolidones, starch glycolates, micro crystallinecellulose, pregelatinized starch, sodium carboxymethyl starch,low-substituted hydroxypropyl cellulose, homopolymers ofN-vinyl-2-pyrrolidone, alkyl-,hydroxyalkyl-, carboxyalkyl-celluloseesters, alginates, microcrystalline cellulose and its polymorphic forms,ion exchange resins, gums, chitin, chitosan, clays, gellan gum,crosslinked polacrillin copolymers, agar, gelatine, dextrines, acrylicacid polymers, carboxymethylcellulose sodium/calcium, hydroxpropylmethyl cellulose phtalate, shellac or mixtures thereof.

Examples of suitable disintegrants are: Ac-Di-Sol®, FMC, USA—which is amodified cellulose gum; Kollidon®CL, BASF, Germany—which is an insolublecrosslinked polyvinlypyrrolidone; Vivastar®, JRS, Germany—which is asodium starch glycolate; MCC Polymorph II (MCC SANAQ Burst®)—PharmatransSanaq AG, Switzerland—which is a stable crystal polymorph type II ofMicrocrystalline cellulose, MCC SANAQ 102 as standard microcrystallinecellulose (MCC).

In one embodiment, the at least one formulating aid is a lubricant,especially an inner-phase lubricant and/or outer-phase lubricant,preferably at least one outer-phase lubricant. Alternatively, the atleast one formulating aid is at least one inner-phase lubricant andouter-phase lubricant.

Said at least one inner-phase lubricant can be selected from the groupcomprising sorbitan esters of fatty acids and polyoxyethylatedhydrogenated castor oil (e.g. the product sold under the trade nameCREMOPHOR®), block copolymers of ethylene oxide and propylene oxide(e.g. products sold under trade names PLURONIC® and POLOXAMER),polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fattyacid esters, sorbitan esters of fatty acids and polyoxyethylene steraricacid esters, stearyl alcohol, glycerol dibehenate, sodium stearylfumarate, glycerol distearate and combinations thereof. Preferably, saidat least one inner-phase lubricant is sodium stearyl fumarate.

Said at least one outer-phase lubricant can be selected from the groupcomprising lecithin, polyoxyethylene stearate, polyoxyethylene sorbitanfatty acid esters, fatty acid salts, mono and diacetyl tartaric acidesters of mono and diglycerides of edible fatty acids, citric acidesters of mono and diglycerides of edible fatty acids, saccharose estersof fatty acids, polyglycerol esters of fatty acids, polyglycerol estersof interesterified castor oil acid (E476), sodium stearoyllactylate,sodium stearoyl fumarate, magnesium and/or calcium stearate,hydrogenated vegetable oils, stearic acid, sodium lauryl sulphate,magnesium lauryl sulphate, colloidal silica, talc and combinationsthereof. Preferably, said at least one outer-phase lubricant ismagnesium and/or calcium stearate, more preferably magnesium stearate.

In one embodiment, the at least one formulating aid is a plasticizer.For example, the plasticizer can be a citrate-based plasticizer selectedfrom the group consisting in triethyl citrate (TEC), tributyl citrate(TBC), acetyl tributyl citrate (ATBC), acetyl triethyl citrate (ATEC)and acetyl tri 2-ethyl-hexyl citrate (ATEHC).

According to a further embodiment, the at least one formulating aid maybe further selected from diluents, film forming agents, adhesives,buffers, adsorbents, natural or synthetic scenting agents, natural orsynthetic flavouring agents, natural or synthetic coloring agents,natural or synthetic sweeteners, natural or synthetic odour-maskingagents, natural or synthetic flavouring- or taste-masking agents,natural and/or synthetic mouthfeel improvers and mixtures thereof.

Suitable natural or synthetic scenting agents include one or morevolatilized chemical compounds, generally at a very low concentration,that humans or other animals perceive by the sense of olfaction.

Suitable natural or synthetic flavoring agents include but are notlimited to mints, such as peppermint, menthol, vanilla, cinnamon,various fruit flavors, both individual or mixed, essential oils such asthymol, eucalyptol, menthol, and methyl salicylate, allylpyrazine,methoxypyrazines, 2-isobutyl-3 methoxypyrazine, acetyl-L-pyrazines,2-acetoxy pyrazine, aldehydes, alcohols, esters, ketones, pyrazines,phenolics, terpenoids and mixtures thereof.

The flavoring agents are generally utilized in amounts that will varydepending upon the individual flavor, and may, for example, range inamount of about 0.5% to about 4% by weight of the final dosage form.

Suitable natural or synthetic coloring agents include, but are notlimited to, titanium dioxide, flavone dyes, iso-quinoline dyes, polyenecolorants, pyran colorants, naphthochinone dyes, chinone andanthrachinone dyes, chromene dyes, benzophyrone dyes as well as indigoiddyes and indole colorants. Examples thereof are caramel coloring,annatto, chlorophyllin, cochineal, betanin, turmeric, saffron, paprika,lycopene, pandan and butterfly pea.

Suitable natural or synthetic sweeteners include but are not limited toxylose, ribose, glucose, mannose, galactose, fructose, dextrose,sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrupsolid, and sugar alcohols such as sorbitol, xylitol, mannitol, andmixtures thereof water soluble artificial sweeteners such as the solublesaccharin salts, i.e. sodium, or calcium saccharin salts, cyclamatesalts, acesulfam-K and the like, and the free acid form of saccharin andaspartame based sweeteners such as L-aspartyl-phenylalanine methylester, Alitame® or Neotame®.

In general, the amount of sweetener will vary with the desired amount ofsweeteners selected for a particular dosage form composition.

Suitable natural and/or synthetic mouthfeel improvers comprise but arenot limited to polyethylenoxide (PEO-1NF), provided by Sumitomo Seika,Osaka, Lot.L20141017A, Hydroxylpropylcellulose (L-HPC LH-11), Shin-Etsu,Japan, Lot.505200, Hydroxypropylethylcellulose (Methocel E15 LV PremiumEP), Lot. LD250012N23, Gummi arabicum Pheur, Roth, Germany,Lot.024208213, or Instant gum AA, Nexira, France or combinationsthereof.

In one embodiment, the at least one formulating aid is provided in atotal amount from about 0.1 wt.-% to about 99.0 wt.-%, preferably fromabout 0.3 wt.-% to about 50.0 wt.-%, even more preferably from about 0.3wt.-% to about 10.0 wt.-%, still more preferably from about 0.3 wt.-% toabout 5.0 wt.-%, and most preferably from about 0.5 wt.-% to about 2.5wt.-% based on the total weight of the surface-reacted calcium carbonateof step a).

If the method comprises the provision of at last one formulating aid,the method for producing a dosage form comprises, preferably consistsof, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules; and    -   e1) mixing the granules obtained in step c) with at least one        formulating aid;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

If the method further comprises a sieving, the method for producing adosage form comprises, preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step c) by at least one mesh size;        and    -   e1) mixing the granules obtained in step d) with at least one        formulating aid;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

Additionally or alternatively, the compacted form of the surface-reactedcalcium carbonate obtained in step b) or the granules obtained in stepc) or, if present, step d) can be loaded with at least one activeingredient and/or inactive precursor thereof.

Thus, in one embodiment, the method further comprises a step e2) ofloading the compacted form obtained in step b) or the granules obtainedin step c) or, if present, step d) with the at least one activeingredient and/or inactive precursor thereof. Preferably, the granulesobtained in step d) are loaded with the at least one active ingredientand/or inactive precursor thereof in loading step e2).

In one embodiment of the present invention, the at least one activeingredient and/or inactive precursor thereof comprises, preferablyconsists of, one active ingredient or inactive precursor thereof.Alternatively, the at least one active ingredient and/or inactiveprecursor thereof comprises, preferably consists of, two or more activeingredient(s) and/or inactive precursor(s) thereof. For example, the atleast one active ingredient and/or inactive precursor thereof comprises,preferably consists of, two or three active ingredient(s) and/orinactive precursor(s) thereof.

Preferably, the at least one active ingredient and/or inactive precursorthereof comprises, preferably consists of, one active ingredient orinactive precursor thereof.

The term “active ingredient” in the meaning of the present inventionrefers to a substance having a specific effect in an organism andcausing a specific reaction in humans, animals, microorganisms and/orplants.

It is appreciated that the at least one active ingredient and/orinactive precursor thereof may be a chiral compound. Thus, the at leastone active ingredient and/or inactive precursor thereof encompasses the(R)-enantiomer, (S)-enantiomer and mixtures thereof, e.g. the racemicmixture.

Additionally or alternatively, the at least one active ingredient and/orinactive precursor thereof may be an isomeric compound. Thus, the atleast one active ingredient and/or inactive precursor thereofencompasses the (Z)-isomer, (E)-isomer and mixtures thereof.

For example, the at least one active ingredient and/or inactiveprecursor thereof is selected from the group comprising fragrances,flavours, herbal extracts, fruit extracts, nutrients, trace minerals,repellents, food, cosmetics, flame retardants, enzymes, macromolecules,pesticides, fertilizers, preserving agents, antioxidants, reactivechemicals, pharmaceutically active agents or pharmaceutically inactiveprecursors of synthetic origin, semi-synthetic origin, natural originthereof, and mixtures thereof.

Fragrances are preferably alcohols, aldehydes and/or ketones having amolecular weight of at least about 100 g/mol and which are useful inimparting an odour, fragrance, essence, or scent either alone or incombination with other fragrances. For example, the fragrance can beselected from the group comprising 2,4-dimethyl-3-cyclohexene-1-methanol(floralol), 2,4-dimethyl cyclohexane methanol (dihydro floralol),5,6-dimethyl-1-methylethenylbicyclo[2.2.1]hept-5-ene-2-methanol(arbozol), α,α,-4-trimethyl-3-cyclohexen-1-methanol (α-terpineol),2,4,6-trimethyl-3-cyclohexene-1-methanol (isocyclo geraniol),4-(1-methylethyl)cyclohexane methanol (mayol),α-3,3-trimethyl-2-norborane methanol,1,1-dimethyl-1-(4-methylcyclohex-3-enyl)methanol, 2-phenylethanol,2-cyclohexyl ethanol, 2-(o-methylphenyl)-ethanol,2-(m-methylphenyl)ethanol, 2-(p-methylphenyl)ethanol,6,6-dimethylbicyclo-[3.1.1]hept-2-ene-2-ethanol (nopol),2-(4-methylphenoxy)-ethanol, 3,3-dimethyl-Δ²-β-norbornane ethanol(patchomint), 2-methyl-2-cyclohexylethanol,1-(4-isopropylcyclohexyl)-ethanol, 1-phenylethanol,1,1-dimethyl-2-phenylethanol, 1,1-dimethyl-2-(4-methyl-phenyl)ethanol,1-phenylpropanol, 3-phenylpropanol, 2-phenylpropanol (HydrotropicAlcohol), 2-(cyclododecyl)propan-1-ol (Hydroxy-ambran),2,2-dimethyl-3-(3-methylphenyl)-propan-1-ol (Majantol),2-methyl-3-phenylpropanol, 3-phenyl-2-propen-1-ol (cinnamyl alcohol),2-methyl-3-phenyl-2-propen-1-ol(methylcinnamyl alcohol),a-n-pentyl-3-phenyl-2-propen-1-ol (a-amyl-cinnamyl alcohol),ethyl-3-hydroxy-3-phenyl propionate, 2-(4-methylphenyl)-2-propanol,3-(4-methylcyclohex-3-ene)butanol,2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)butanol,2-ethyl-4-(2,2,3-trimethyl-cyclopent-3-enyl)-2-buten-1-ol,3-methyl-2-buten-1-ol(prenol),2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol, ethyl3-hydroxybutyrate, 4-phenyl-3-buten-2-ol, 2-methyl-4-phenylbutan-2-ol,4-(4-hydroxyphenyl)butan-2-one,4-(4-hydroxy-3-methoxyphenyl)-butan-2-one, 3-methyl-pentanol,3-methyl-3-penten-1-ol, 1-(2-propenyl)cyclopentan-1-ol (plinol),2-methyl-4-phenylpentanol (Pamplefleur), 3-methyl-5-phenylpentanol(Phenoxanol), 2-methyl-5-phenylpentanol,2-methyl-5-(2,3-dimethyltricyclo[2.2.1.0.sup.(2,6)]hept-3-yl)-2-penten-1-ol(santalol),4-methyl-1-phenyl-2-pentanol,5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol (sandalore),(1-methyl-bicyclo[2.1.1]hepten-2-yl)-2-methylpent-1-en-3-ol,3-methyl-1-phenylpentan-3-ol,1,2-dimethyl-3-(1-methylethenyl)cyclopentan-1-ol,2-isopropyl-5-methyl-2-hexenol, cis-3-hexen-1-ol, trans-2-hexen-1-ol,2-isoproenyl-4-methyl-4-hexen-1-ol (Lavandulol),2-ethyl-2-prenyl-3-hexenol, 1-hydroxymethyl-4-iso-propenyl-1-cyclohexene(Dihydrocuminyl alcohol),1-methyl-4-isopropenylcyclohex-6-en-2-ol(carvenol),6-methyl-3-isopropenylcyclohexan-1-ol (dihydrocarveol),1-methyl-4-iso-propenylcyclohexan-3-ol,4-isopropyl-1-methylcyclohexan-3-ol, 4-tert-butylcyclo-hexanol,2-tert-butylcyclohexanol, 2-tert-butyl-4-methylcyclohexanol (rootanol),4-isopropyl-cyclohexanol, 4-methyl-1-(1-methylethyl)-3-cyclohexen-1-ol,2-(5,6,6-trimethyl-2-norbornyl)cyclohexanol, isobornylcyclohexanol,3,3,5-trimethylcyclohexanol, 1-methyl-4-isopropylcyclohexan-3-ol,1-methyl-4-isopropylcyclohexan-8-ol (dihydroterpineol),1,2-dimethyl-3-(1-methylethyl)cyclohexan-1-ol, heptanol,2,4-dimethylheptan-1-ol, 6-heptyl-5-hepten-2-ol (isolinalool),2,4-dimethyl-2,6-heptandienol,6,6-dimethyl-2-oxymethyl-bicyclo[3.1.1]hept-2-ene (myrcenol),4-methyl-2,4-heptadien-1-ol, 3,4,5,6,6-pentamethyl-2-heptanol,3,6-dimethyl-3-vinyl-5-hepten-2-ol,6,6-dimethyl-3-hydroxy-2-methylenebicyclo[3.1.1]heptane,1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol, 2,6-dimethylheptan-2-ol(dimetol), 2,6,6-trimethylbicyclo[1.3.3]heptan-2-ol, octanol, 2-octenol,2-methyloctan-2-ol, 2-methyl-6-methylene-7-octen-2-ol (myrcenol),7-methyloctan-1-ol, 3,7-dimethyl-6-octenol, 3,7-dimethyl-7-octenol,3,7-dimethyl-6-octen-1-ol (citronellol),3,7-dimethyl-2,6-octadien-1-ol(geraniol), 3,7-dimethyl-2,6-octadien-1-ol(nerol), 3,7-dimethyl-7-methoxyoctan-2-ol(osyrol),3,7-dimethyl-1,6-octadien-3-ol (linalool),3,7-dimethyloctan-1-ol(pelargol), 3,7-dimethyloctan-3-ol(tetrahydrolinalool), 2,4-octadien-1-ol, 3,7-dimethyl-6-octen-3-ol(dihydrolinalool), 2,6-dimethyl-7-octen-2-ol (dihydromyrcenol),2,6-dimethyl-5,7-octadien-2-ol, 4,7-dimethyl-4-vinyl-6-octen-3-ol,3-methyloctan-3-ol, 2,6-dimethyloctan-2-ol, 2,6-dimethyloctan-3-ol,3,6-dimethyloctan-3-ol, 2,6-dimethyl-7-octen-2-ol,2,6-dimethyl-3,5-octadien-2-ol(muguol), 3-methyl-1-octen-3-ol,7-hydroxy-3,7-dimethyloctanal, 3-nonanol, 2,6-nonadien-1-ol,cis-6-nonen-1-ol, 6,8-dimethylnonan-2-ol, 3-(hydroxymethyl)-2-nonanone,2-nonen-1-ol, 2,4-nonadien-1-ol, 3,7-dimethyl-1,6-nonadien-3-ol,decanol, 9-decenol, 2-benzyl-M-dioxa-5-ol, 2-decen-1-ol,2,4-decadien-1-ol, 4-methyl-3-decen-5-ol,3,7,9-trimethyl-1,6-decadien-3-ol (isobutyl linalool), undecanol,2-undecen-1-ol, 10-undecen-1-ol, 2-dodecen-1-ol, 2,4-dodecadien-1-ol,2,7,11-trimethyl-2,6,10-dodecatrien-1-ol (farnesol),3,7,11-trimethyl-1,6,10,-dodecatrien-3-ol (nerolidol),3,7,11,15-tetramethylhexadec-2-en-1-ol (phytol),3,7,11,15-tetramethylhexadec-1-en-3-ol (iso phytol), benzyl alcohol,p-methoxy benzyl alcohol (anisyl alcohol), para-cymen-7-ol (cuminylalcohol), 4-methyl benzyl alcohol, 3,4-methylenedioxy benzyl alcohol,methyl salicylate, benzyl salicylate, cis-3-hexenyl salicylate, n-pentylsalicylate, 2-phenylethyl salicylate, n-hexyl salicylate,2-methyl-5-isopropylphenol, 4-ethyl-2-methoxyphenol,4-allyl-2-methoxyphenol (eugenol), 2-methoxy-4-(1-propenyl)phenol(isoeugenol), 4-allyl-2,6-dimethoxy-phenol, 4-tert-butylphenol,2-ethoxy-4-methylphenol, 2-methyl-4-vinylphenol,2-isopropyl-5-methylphenol (thymol), pentyl-ortho-hydroxy benzoate,ethyl 2-hydroxy-benzoate, methyl 2,4-dihydroxy-3,6-dimethylbenzoate,3-hydroxy-5-methoxy-1-methylbenzene,2-tert-butyl-4-methyl-1-hydroxybenzene,1-ethoxy-2-hydroxy-4-propenylbenzene, 4-hydroxytoluene,4-hydroxy-3-methoxybenzaldehyde, 2-ethoxy-4-hydroxybenzaldehyde,decahydro-2-naphthol, 2,5,5-trimethyl-octahydro-2-naphthol,1,3,3-trimethyl-2-norbornanol(fenchol),3a,4,5,6,7,7a-hexahydro-2,4-dimethyl-4,7-methano-1H-inden-5-ol,3a,4,5,6,7,7a-hexahydro-3,4-dimethyl-4,7-methano-1H-inden-5-ol,2-methyl-2-vinyl-5-(1-hydroxy-1-methylethyl)tetra-hydrofuran,β-caryophyllene alcohol, vanillin, ethyl vanillin, cinnamaldehyde,benzaldehyde, phenyl acetaldehyde, heptylaldehyde, octylaldehyde,decylaldehyde, undecylaldehyde, undecylenic aldehyde, dodecylaldehyde,tridecylaldehyde, methylnonyl aldehyde, didecylaldehyde, anisaldehyde,citronellal, citronellyloxyaldehyde, cyclamen aldehyde, α-hexylcinnamaldehyde, hydroxycitronellal, α-methyl cinnamaldehyde, methylnonylacetaldehyde, propylphenyl aldehyde, citral, perilla aldehyde,tolylaldehyde, tolylacetaldehyde, cuminaldehyde, LILIAL®, salicylaldehyde, α-amylcinnamaldehyde and heliotropin and mixtures thereof.

Various essential oils, herbal extracts and/or fruit extracts may alsobe used, preferably those with various medicinal or dietary supplementproperties. Essential oils, herbal extracts and/or fruit extracts aregenerally extracts or aromatic plants, plant parts, fruit or fruit partsthat can be used medicinally or for flavouring. Suitable herbal extractsand/or fruit extracts can be used singly or in various mixtures.

Commonly used essential oils, herbal extracts and/or fruit extractsinclude Echinacea, Goldenseal, Calendula, Rosemary, Thyme, Kava Kava,Aloe, Blood Root, Grapefruit Seed Extract, Black Cohosh, Ginseng,Guarana, Cranberry, Ginko Biloba, St. John's Wort, Evening Primrose Oil,Yohimbe Bark, Green Tea, Ma Huang, Maca, Bilberry, Lutein, Ginger,eugenol-containing oils and combinations thereof.

A variety of nutrients may be used including virtually any vitamin,mineral and/or phytochemical. For example, vitamin A, vitamin B1,vitamin B6, vitamin B12, vitamin B2, vitamin B6, vitamin D, vitamin E,i.e. tocopheroles, vitamin K, thiamine, riboflavin, biotin, folic acid,niacin, pantothenic acid, Q10, alpha lipoic acid, dihydrolipoic acid,curcumin, xanthophylls, beta cryptoxanthin, lycopene, lutein,zeaxanthin, astaxanthin, beta-carotene, carotenes, mixed carotenoids,polyphenols, flavonoids, sodium, potassium, calcium, magnesium, sulphur,chlorine, choline, and/or phytochemicals such as carotenoids,chlorophyll, chlorophyllin, fibre, flavanoids, anthocyanins, cyaniding,delphinidin, malvidin, pelargonidin, peonidin, petunidin, flavanols,catechin, epicatechin, epigallocatechin, epigallocatechingallate,theaflavins, thearubigins, proanthocyanins, flavonols, quercetin,kaempferol, myricetin, isorhamnetin, flavononeshesperetin, naringenin,eriodictyol, tangeretin, flavones, apigenin, luteolin, lignans,phytoestrogens, resveratrol, isoflavones, daidzein, genistein,glycitein, soy isoflavones, and combinations thereof, may be used.Examples of nutrients that can be used as active ingredient(s) are setforth in U.S. Patent Application Publication Nos. 2003/0157213 A1,2003/0206993 and 2003/0099741 A1 which are incorporated in theirentirety herein by reference for all purposes.

In one embodiment, trace minerals can be used, e.g. manganese, zinc,copper, fluorine, molybdenum, iodine, cobalt, chromium, selenium,phosphorous, and combinations thereof.

Enzymes can include but are not limited to coenzyme Q10, pepsin,phytase, trypsin, lipases, proteases, cellulases, lactase andcombinations thereof. Macromolecules are preferably known proteins,antibodies, receptors, carries, polypeptides, peptides, probiotics orlipids.

Pesticides are preferably any known herbicide, insecticide, insectgrowth regulator, nematicide, termiticide, molluscicide, piscicide,avicide, rodenticide, predacide, bactericide, insect repellent, animalrepellent, antimicrobial, fungicide, disinfectant (antimicrobial), andsanitizer known to the skilled person.

It is to be noted that the preserving agent may be any such compoundknown to the skilled person. For example, preserving agents may include,but are not limited to, phenoxyethanol, ethylhexylglycerin, parabenssuch as methyl paraben, ethyl paraben, propyl paraben, butyl paraben andmixtures thereof, benzalkonium chloride, chlorbutanol, benzyl alcohol,cetylpyridinium chloride, tartaric acid, lactic acid, malic acid, aceticacid, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate andmixtures thereof.

Antioxidants are preferably selected from the group comprisingbutylhydroxyanisol (BHA), butylhydroxytoluol (BHT), gallate, carotinoid,polyphenols such as resveratrol, flavonoid and mixtures thereof,derivatives of polyphenols, tocopherol and salts thereof, betacarotin,ubichinon, tocotrienol, dihydroquercetin, antioxidants of natural originand mixtures thereof. If the antioxidant is of natural origin, theantioxidant can be e.g. a conifer extract, pinus pinaster bark extractsuch as Pycnogenol® from Horphag, Switzerland, and/or emblicaofficinalis fruit extract such as Saberry® from Sabinsa corporation,Germany.

The pharmaceutically active agent or pharmaceutically inactive precursorthereof is preferably selected from the group comprisingpharmaceutically active agent or pharmaceutically inactive precursor ofsynthetic origin, semi-synthetic origin, natural origin and combinationsthereof.

Thus, a pharmaceutically active agent refers to pharmaceutically activeagents which are of synthetic origin, semi-synthetic origin, naturalorigin and combinations thereof. Further, a pharmaceutically inactiveprecursor of the pharmaceutically active agent refers topharmaceutically inactive precursors which are of synthetic origin,semi-synthetic origin, natural origin and combinations thereof and willbe activated at a later stage to the respective pharmaceutically activeagent.

The conversion or activation of such pharmaceutically active or inactiveprodrugs is known to the skilled person and commonly in use, e.g.conversion and activation in the stomach and/or gastro-intestinalpathway—such as for examples by ph-mediated or enzymatic-mediatedactivation.

It lies within the understanding of the skilled person that thementioned activation methods are of mere illustrative character and arenot intended to be of limiting character.

It is to be noted that the pharmaceutically active agent orpharmaceutically inactive precursor thereof, may be any such compoundknown to the skilled person.

Pharmaceutically active agents thus include any compound that providesprophylactic and/or therapeutic properties when administered to humansand/or animals. Examples include, but are not limited to, pharmaceuticalactives, therapeutic actives, veterinarian actives, nutraceuticals, andgrowth regulators and the corresponding active or inactive precursorthereof.

For example, the pharmaceutically active agent or pharmaceuticallyinactive precursor thereof can be an anti-inflammatory agent. Suchagents may include, but are not limited to, non-steroidalanti-inflammatory agents or NSAIDs, such as propionic acid derivatives;acetic acid derivatives; fenamic acid derivatives; biphenylcarboxylicacid derivatives; and oxicams. All of these NSAIDs are fully describedin U.S. Pat. No. 4,985,459 to Sunshine et al., incorporated by referenceherein in its entirety as to the description of such NSAIDs. Examples ofuseful NSAIDs include acetylsalicylic acid, ibuprofen, naproxen,benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen,indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, microprofen,tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen,bucloxic acid and mixtures thereof.

Also useful are the steroidal anti-inflammatory drugs such ashydrocortisone and the like, and COX-2 inhibitors such as meloxicam,celecoxib, rofecoxib, valdecoxib, etoricoxib or mixtures thereof.Mixtures of any of the above anti-inflammatories may be used.

Other materials that can be used as pharmaceutically active agent orpharmaceutically inactive precursor thereof include commonly known mouthand throat products. These products include, but are not limited to,upper respiratory agents such as phenylephrine, diphenhydramine,dextromethorphan, bromhexine and chiorpheniramine, gastrointestinalagents such as famotidine, loperamide and simethicone, anti-fungals suchas miconazole nitrate, antibiotics and analgesics such as ketoprofen andfluribuprofen.

The at least one pharmaceutically active agent or pharmaceuticallyinactive precursor thereof may be an anti-tartar agent. Anti-tartaragents useful herein include phosphates. Phosphates includepyrophosphates, polyphosphates, polyphosphonates and mixtures thereof.Pyrophosphates are among the best known phosphates for use in dentalcare products. Pyrophosphate ions delivered to the teeth derive frompyrophosphate salts. The pyrophosphate salts useful in the presentpharmaceutical delivery system include the dialkali metal pyrophosphatesalts, tetra-alkali metal pyrophosphate salts, and mixtures thereof.Disodium dihydrogen pyrophosphate (Na₂H₂P₂O₇), tetrasodium pyrophosphate(Na₄P₂O₇), and tetrapotassium pyrophosphate (K₄P₂O₇) in theirnon-hydrated as well as hydrated forms are preferred. Anticalculusphosphates include potassium and sodium pyrophosphates; sodiumtripolyphosphate; diphosphonates, such asethane-1-hydroxy-1,I-diphosphonate; 1-azacycloheptane-1,1-diphosphonate;and linear alkyl diphosphonates; linear carboxylic acids and sodium andzinc citrate.

The pharmaceutically active agent or pharmaceutically inactive precursorthereof may be also selected from sodium pyrosulphite,butylhydroxytoluene, butylated hydroxyanisole.

The pharmaceutically active agent or pharmaceutically inactive precursorthereof may be also selected from ephedrine, magaldrate,pseudoephedrine, sildenafil, xylocaine, benzalconium chloride, caffeine,phenylephrine, amfepramone, orlistat, sibutramine, acetaminophen,aspirin, glitazones, metformin, chlorpromazine, dimenhydrinat,domperidone, meclozine, metoclopramide, odansetron, prednisolone,promethazine, acrivastine, cetirizine, cinnarizine, clemastine,cyclizine, desloratadine, dexchlorpheniramine, dimenhydrinate, ebastine,fexofenadine, ibuprofen, levolevoproricin, loratadine, meclozine,mizolastine, promethazine, miconazole, chlorhexidine diacetate,fluoride, decapeptide KSL, aluminium fluoride, aminochelated calcium,ammonium fluoride, ammonium fluorosilicate, ammonium monofluorphosphate,calcium fluoride, calcium gluconate, calcium glycerophosphate, calciumlactate, calcium monofluorphosphate, calciumcarbonate, carbamide, cetylpyridinium chloride, chlorhexidine, chlorhexidine digluconate,chlorhexidine chloride, chlorhexidine diacetate, CPP caseine phosphopeptide, hexetedine, octadecentyl ammonium fluoride, potassiumfluorosilicate, potassium chloride, potassium monofluorphosphate, sodiumbi carbonate, sodium carbonate, sodium fluoride, sodium fluorosilicate,sodium monofluorphosphate, sodium tri polyphosphate, stannous fluoride,stearyl trihydroxyethyl propylenediamine dihydrofluoride, strontiumchloride, tetra potassium pyrophosphate, tetra sodium pyrophosphate,tripotassium orthophosphate, trisodium orthophosphate, alginic acid,aluminium hydroxide, sodium bicarbonate, sildenafil, tadalafil,vardenafil, yohimbine, cimetidine, nizatidine, ranitidine,acetylsalicylic acid, clopidogrel, acetylcysteine, bromhexine, codeine,dextromethorphan, diphenhydramine, noscapine, phenylpropanolamine,vitamin D, simvastatin, bisacodyl, lactitol, lactulose, magnesium oxide,sodium picosulphate, senna glycosides, benzocaine, lidocaine,tetracaine, almotriptan, eletriptan, naratriptan, rizatriptan,sumatriptan, zolmitriptan, calcium, chromium, copper, iodine, magnesium,manganese, molybdenium, phosphor, selenium, zinc, chloramine,hydrogenperoxide, metronidazole, triamcinolonacetonide, benzethoniumchl., cetyl pyrid. chl., chlorhexidine, fluoride, lidocaine,amphotericin, miconazole, nystatin, fish oil, ginkgo biloba, ginseng,ginger, purple coneflower, saw palmetto, cetirizine, levocetirizine,loratadine, diclofenac, flurbiprofen, acrivastine pseudoephedrine,loratadine pseudoephedrine, glucosamine, hyaluronic acid, decapeptideKSL-W, decapeptide KSL, resveratrol, misoprostol, bupropion, ondansetronHCl, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole,bacteria and the like, loperamide, simethicone, acetylsalicylic acid andothers, sucralfate, clotrimazole, fluconazole, itraconazole,ketoconazole, terbinafine, allopurinol, probenecid, atorvastatin,fluvastatin, lovastatin, nicotinic acid, pravastatin, rosuvastatin,simvastatin, pilocarpine, naproxen, alendronate, etidronate, raloxifene,risedronate, benzodiazepines, disulphiram, naltrexone, buprenorphine,codeine, dextropropoxyphene, fentanyl, hydromorphone, ketobemidone,ketoprofen, methadone, morphine, naproxen, nicomorphine, oxycodone,pethidine, tramadol, amoxicillin, ampicillin, azithromycin,ciprofloxacin, clarithromycin, doxycyclin, erythromycin, fusidic acid,lymecycline, metronidazole, moxifloxacin, ofloxacin, oxytetracycline,phenoxymethylpenicillin, rifamycins, roxithromycin, sulphamethizole,tetracycline, trimethoprim, vancomycin, acarbose, glibenclamide,gliclazide, glimepiride, glipizide, insulin, repaglinide, tolbutamide,oseltamivir, aciclovir, famciclovir, penciclovir, valganciclovir,amlopidine, diltiazem, felodipine, nifedipine, verapamil, finasteride,minoxidil, cocaine, buphrenorphin, clonidine, methadone, naltrexone,calcium antagonists, clonidine, ergotamine, β-blockers, aceclofenac,celecoxib, dexiprofen, etodolac, indometacin, ketoprofen, ketorolac,lornoxicam, meloxicam, nabumetone, oiroxicam, parecoxib, phenylbutazone,piroxicam, tiaprofenic acid, tolfenamic acid, aripiprazole,chlorpromazine, chlorprothixene, clozapine, flupentixol, fluphenazine,haloperidol, lithium carbonate, lithium citrate, melperone, penfluridol,periciazine, perphenazine, pimozide, pipamperone, prochlorperazine,risperidone, thioridizin, fluconazole, itraconazole, ketoconazole,voriconazole, opium, benzodiazepines, hydroxine, meprobamate,phenothiazine, aluminiumaminoacetate, esomeprazole, famotidine,magnesium oxide, nizatide, omeprazole, pantoprazole, fluconazole,itraconazole, ketoconazole, metronidazole, amphetamine, atenolol,bisoprolol fumarate, metoprolol, metropolol, pindolol, propranolol,auranofin, and bendazac.

Further examples of useful pharmaceutically active agents orpharmaceutically inactive precursors thereof can include activeingredients selected from the therapeutical groups comprising:Analgesic, Anaesthetic, Antipyretic, Anti-allergic, Anti-arrhythmic,Appetite suppressant, Antifungal, Anti-inflammatory, Broncho dilator,Cardiovascular drugs, Coronary dilator, Cerebral dilator, Peripheralvasodilator, Anti-infective, Psychotropic, Anti-manic, Stimulant,Antihistamine, Laxative, Decongestant, Gastro-intestinal sedative,Sexual dysfunction agent, Disinfectants, Anti-diarrhoeal, Anti-anginalsubstance, Vasodilator, Anti-hypertensive agent, Vasoconstrictor,Migraine treating agent, Antibiotic, Tranquilizer, Antipsychotic,Anti-tumour drug, Anticoagulant, Antithrombotic agent, Hypnotic,Sedative, Anti-emetic, Anti-nauseant, Anticonvulsant, Neuromuscularagent, Hyper and hypoglycaemic, Thyroid and antithyroid, Diuretic,Antispasmodic, Uterine relaxant, Anti-obesity agent, Anorectic,Spasnolytics, Anabolic agent, Erythropoietic agent, Anti-asthmatic,Expectorant, Cough suppressant, Mucolytic, Anti-uricemic agent, Dentalvehicle, Breath freshener, Antacid, Anti-diuretic, Anti-flatulent,Betablocker, Teeth Whitener, Enzyme, Co-enzyme, Protein, Energy booster,Fibre, Probiotics, Prebiotics, NSAID, Anti-tussives, Decongestants,Anti-histamines, Expectorants, Anti-diarrhoeals, Hydrogen antagonists,Proton pump inhibitors, General nonselective CNS depressants, Generalnonselective CNS stimulants, Selectively CNS function modifying drugs,Antiparkinsonism, Narcotic-analgetics, Analgetic-antipyretics,Psychopharmacological drugs, and Sexual dysfunction agents.

Examples of useful pharmaceutically active agents or pharmaceuticallyinactive precursors thereof may also include: Casein glyco-macro-peptide(CGMP), Triclosan, Cetyl pyridinium chloride, Domiphen bromide,Quaternary ammonium salts, zinc components, Sanguinarine, Fluorides,Alexidine, Octonidine, EDTA, Aspirin, Acetaminophen, Ibuprofen,Ketoprofen, Diflunisal, Fenoprofen calcium, Naproxen, Tolmetin sodium,Indomethacin, Benzonatate, Caramiphen edisylate, Menthol,Dextromethorphan hydrobromide, Theobromine hydrochloride, ChlophendianolHydrochloride, Pseudoephedrine Hydrochloride, Phenylephrine,Phenylpropanolamine, Pseudoephedrine sulphate, Brompheniramine maleate,Chlorpheniramine-maleate, Carbinoxamine maleate, Clemastine fumarate,Dexchlorpheniramine maleate, Dephenhydramine hydrochloride,Diphenpyralide hydrochloride, Azatadine maleate, Diphenhydraminecitrate, Doxylamine succinate, Promethazine hydrochloride, Pyrilaminemaleate, Tripellenamine citrate, Triprolidine hydrochloride,Acrivastine, Loratadine, Brompheniramine, Dexbrompheniamine,Guaifenesin, Ipecac, potassium iodide, Terpin hydrate, Loperamide,Famotidine, Ranitidine, Omeprazole, Lansoprazole, Aliphatic alcohols,Barbiturates, caffeine, strychnine, Picrotoxin, Pentyenetetrazol,Phenyhydantoin, Phenobarbital, Primidone, Carbamazapine, Etoxsuximide,Methsuximide, Phensuximide, Trimethadione, Diazepam, Benzodiazepines,Phenacemide, Pheneturide, Acetazolamide, Sulthiame, bromide, Levodopa,Amantadine, Morphine, Heroin, Hydromorphone, Metopon, Oxymorphone,Levophanol, Codeine, Hydrocodone, Xycodone, Nalorphine, Naloxone,Naltrexone, Salicylates, Phenylbutazone, Indomethacin, Phenacetin,Chlorpromazine, Methotrimeprazine, Haloperidol, Clozapine, Reserpine,Imipramine, Tranylcypromine, Phenelzine, Lithium, Sildenafil citrate,Tadalafil, and Vardenafil CL. For example, eugenol can be used asanaesthetic.

Examples of useful pharmaceutically active agent or pharmaceuticallyinactive precursor thereof may include active ingredients selected fromthe groups of ace-inhibitors, antianginal drugs, anti-arrhythmias,anti-asthmatics, anti-cholesterolemics, analgesics, anaesthetics,anticonvulsants, anti-depressants, anti-diabetic agents, anti-diarrhoeapreparations, antidotes, anti-histamines, anti-hypertensive drugs,anti-inflammatory agents, anti-lipid agents, anti-manics,anti-nauseants, anti-stroke agents, anti-thyroid preparations,anti-tumour drugs, anti-viral agents, acne drugs, alkaloids, amino acidpreparations, anti-tussives, anti-uricemic drugs, anti-viral drugs,anabolic preparations, systemic and non-systemic anti-infective agents,anti-neoplasties, antiparkinsonian agents, anti-rheumatic agents,appetite stimulants, biological response modifiers, blood modifiers,bone metabolism regulators, cardiovascular agents, central nervoussystem stimulates, cholinesterase inhibitors, contraceptives,decongestants, dietary supplements, dopamine receptor agonists,endometriosis management agents, enzymes, erectile dysfunction therapiessuch as sildenafil citrate, which is currently marketed as Viagra™,fertility agents, gastrointestinal agents, homeopathic remedies,hormones, hypercalcemia and hypocalcemia management agents,immunomodulators, immunosuppressives, migraine preparations, motionsickness treatments, muscle relaxants, obesity management agents,osteoporosis preparations, oxytocics, parasympatholytics,parasympathomimetics, prostaglandins, psychotherapeutic agents,respiratory agents, sedatives, smoking cessation aids such asbromocriptine, sympatholytics, tremor preparations, urinary tractagents, vasodilators, laxatives, antacids, ion exchange resins,anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents,anti-ulcer agents, anti-inflammatory substances, coronary dilators,cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants,anti-hypertensive drugs, vasoconstrictors, migraine treatments,antibiotics, tranquilizers, anti-psychotics, anti-tumour drugs,anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics,anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- andhypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics,anti-spasmodics, terine relaxants, anti-obesity drugs, erythropoieticdrugs, anti-asthmatics, cough suppressants, mucolytics, DNA and geneticmodifying drugs, and combinations thereof.

Examples of useful pharmaceutically active agents or pharmaceuticallyinactive precursors thereof contemplated can also include antacids,H2-antagonists, and analgesics. For example, antacid dosages can beprepared using the ingredients calcium carbonate alone or in combinationwith magnesium hydroxide, and/or aluminium hydroxide. Moreover, antacidscan be used in combination with H2-antagonists.

Analgesics include opiates and opiate derivatives, such as Oxycontin™,ibuprofen, aspirin, acetaminophen, and combinations thereof that mayoptionally include caffeine.

Other useful pharmaceutically active agents or pharmaceutically inactiveprecursors thereof can include anti-diarrhoeals such as Immodium™ AD,anti-histamines, anti-tussives, decongestants, vitamins, and breathfresheners. Also contemplated for use herein are anxiolytics such asXanax™; anti-psychotics such as Clozaril™ and Haldol™; non-steroidalanti-inflammatories (NSAID's) such as ibuprofen, naproxen sodium,Voltaren™ and Lodine™, anti-histamines such as Claritin™, Hismanal™,Relafen™, and Tavist™; antiemetics such as Kytril™ and Cesamet™;bronchodilators such as Bentolin™, Proventil™; anti-depressants such asProzac™, Zoloft™, and Paxil™; anti-migraines such as Imigra™,ACE-inhibitors such as Vasotec™, Capoten™ and Zestril™; anti-Alzheimer'sagents, such as Nicergoline™; and CaH-antagonists such as Procardia™,Adalat™, and Calan™.

The popular H2-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine hydrochloride, famotidine,nizatidine, ebrotidine, mifentidine, roxatidine, pisatidine andaceroxatidine.

Active antacid ingredients can include, but are not limited to, thefollowing: aluminium hydroxide, dihydroxyaluminium aminoacetate,aminoacetic acid, aluminium phosphate, dihydroxyaluminium sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuthsubsilysilate, calcium phosphate, citrate ion (acid or salt), aminoacetic acid, hydrate magnesium aluminate sulphate, magaldrate, magnesiumaluminosilicate, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, magnesium trisilicate, milk solids,aluminium mono-ordibasic calcium phosphate, tricalcium phosphate,potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesiumaluminosilicates, tartaric acids and salts.

In some embodiments, the pharmaceutically active agent orpharmaceutically inactive precursor thereof can be selected fromanalgesics/anaesthetics such as menthol, phenol, hexylresorcinol,benzocaine, dyclonine hydrochloride, benzyl alcohol, salicyl alcohol,and combinations thereof. In some embodiments, the pharmaceuticallyactive agent or pharmaceutically inactive precursor thereof can beselected from demulcents such as slippery elm bark, pectin, gelatin, andcombinations thereof. In some embodiments, the pharmaceutically activeagent or pharmaceutically inactive precursor thereof can be selectedfrom antiseptic ingredients such as cetylpyridinium chloride, domiphenbromide, dequalinium chloride, eugenol and combinations thereof.

In some embodiments, the pharmaceutically active agent orpharmaceutically inactive precursor thereof can be selected fromantitussive ingredients such as chlophedianol hydrochloride, codeine,codeine phosphate, codeine sulphate, dextromethorphan, dextromethorphanhydrobromide, diphenhydramine citrate, and diphenhydraminehydrochloride, and combinations thereof.

In some embodiments, the pharmaceutically active agent orpharmaceutically inactive precursor thereof can be selected from throatsoothing agents such as honey, propolis, aloe vera, glycerine, mentholand combinations thereof. In still other embodiments, thepharmaceutically active agent or pharmaceutically inactive precursorthereof can be selected from cough suppressants. Such cough suppressantscan fall into two groups: those that alter the texture or production ofphlegm such as mucolytics and expectorants; and those that suppress thecoughing reflex such as codeine (narcotic cough suppressants),antihistamines, dextromethorphan and isoproterenol (non-narcotic coughsuppressants).

In still other embodiments, the pharmaceutically active agent orpharmaceutically inactive precursor thereof can be an antitussiveselected from the group comprising codeine, dextromethorphan,dextrorphan, diphenhydramine, hydrocodone, noscapine, oxycodone,pentoxyverine and combinations thereof. In some embodiments, thepharmaceutically active agent or pharmaceutically inactive precursorthereof can be selected from antihistamines such as acrivastine,azatadine, brompheniramine, chlo[phi]heniramine, clemastine,cyproheptadine, dexbrompheniramine, dimenhydrinate, diphenhydramine,doxylamine, hydroxyzine, meclizine, phenindamine, phenyltoloxamine,promethazine, pyrilamine, tripelennamine, triprolidine and combinationsthereof. In some embodiments, the pharmaceutically active agent orpharmaceutically inactive precursor thereof can be selected fromnon-sedating antihistamines such as astemizole, cetirizine, ebastine,fexofenadine, loratidine, terfenadine, and combinations thereof.

For example, the at least one active ingredient and/or inactiveprecursor thereof is selected from fragrances, flavours, essential oils,insecticide, fungicide, pharmaceutically active agent, orpharmaceutically inactive precursor thereof, e.g. antiseptic and/oranaesthetic, and mixtures thereof. Most preferably, the at least oneactive ingredient and/or inactive precursor thereof is apharmaceutically active agent, or pharmaceutically inactive precursorthereof, e.g. antiseptic and/or anaesthetic, or a mixture thereof.

It is preferred that the at least one active ingredient and/or inactiveprecursor thereof is in liquid form.

The term “liquid” in the meaning of the present invention refers to anon-gaseous fluid composition, comprising or consisting of the at leastone active ingredient and/or inactive precursor thereof, which isreadily flowable at the pressure conditions and temperature of use, i.e.the temperature at which the method, preferably method step e2), iscarried out.

It is appreciated that the at least one active ingredient and/orinactive precursor thereof can be used as such provided that it is inliquid form or in a solvent. If the at least one active ingredientand/or inactive precursor thereof is solid at room temperature, the atleast one active ingredient and/or inactive precursor thereof ispreferably provided in a (aqueous or organic) solvent such as to form asolution, a dispersion, e.g. a nano-dispersion, an emulsion, e.g. anano-emulsion, or suspension, e.g. a nano-suspension.

If the at least one active ingredient and/or inactive precursor thereofis provided in a solvent, the solvent is preferably selected from thegroup comprising water, methanol, ethanol, n-butanol, isopropanol,n-propanol, n-octanol, acetone, dimethylsulphoxide, dimethylformamide,tetrahydrofurane, vegetable oils and the derivatives thereof, animaloils and the derivatives thereof, molten fats and waxes, and mixturesthereof, and more preferably the solvent is water, ethanol and/oracetone. More preferably, the solvent is ethanol and/or acetone.

If the at least one active ingredient and/or inactive precursor thereofis solid at room temperature, the at least one active ingredient and/orinactive precursor thereof can be also provided in a melted state, i.e.the at least one active ingredient and/or inactive precursor thereof ispreferably provided in a melted state if the melting temperature isbelow 180° C., preferably from 20 to 100° C.

If the at least one active ingredient and/or inactive precursor thereofis liquid as such, the at least one active ingredient and/or inactiveprecursor thereof is preferably liquid in a temperature range from above0° C., such as in a range from 3 to 180° C., preferably from 10 to 100°C. and most preferably from 10 to 40° C. For example, the at least oneactive ingredient and/or inactive precursor thereof is liquid in atemperature range from above 0° C., such as in a range from 3 to 180°C., preferably from 10 to 100° C. and most preferably from 10 to 40° C.,at ambient pressure conditions, i.e. at atmospheric pressure.

In one embodiment, the at least one active ingredient and/or inactiveprecursor thereof is dissolved in a solvent. That is to say, the atleast one active ingredient and/or inactive precursor thereof and thesolvent form a system in which no discrete solid particles are observedin the solvent and thus form a “solution”.

The term “suspension” refers to a system comprising essentiallyinsoluble solids and solvent and optionally further additives andusually contains large amounts of solids and, thus, is more viscous andgenerally of higher density than the solvent from which it is formed.However, the term “essentially insoluble” does not exclude that at leasta part of the solids material dissolves in water under certainconditions, e.g. at increased temperature.

If the at least one active ingredient and/or inactive precursor thereofis provided in a solvent, the solvent is preferably removed directlyafter method step e2), e.g. by evaporation. The term “directly after”means that no further step is implemented between loading step e2) andthe defined removing of the solvent. However, it is appreciated that theremoval of the solvent can be timely separated from method step e2).

In step e2) of the method of the present invention, the compacted formof the surface-reacted calcium carbonate obtained in step b) or thegranules obtained in step c) or, if present, step d) is/are loaded withthe at least one active ingredient and/or inactive precursor thereof.For example, the granules obtained in step d) are loaded with the atleast one active ingredient and/or inactive precursor thereof.

Preferably, loading step e2) is carried out by spraying or dropping theat least one active ingredient and/or inactive precursor thereof ontothe compacted form of the surface-reacted calcium carbonate obtained instep b) or the granules obtained in step c) or, if present, step d) andmixing in a device which is suitable for evenly distributing the atleast one active ingredient and/or inactive precursor thereof onto thecompacted form of the surface-reacted calcium carbonate or the granules.

For the purposes of the present invention, any suitable means known inthe art may be used. However, loading step e2) preferably takes place ina device selected from the group comprising fluidized beddryers/granulators, ploughshare mixer, vertical or horizontal mixers,high or low shear mixer and high speed blenders.

It is appreciated that loading step e2) can be carried out over a broadtemperature and/or pressure range. For example, loading step e2) iscarried out in a temperature range from above 0° C., such as in a rangefrom 3 to 180° C., preferably from 10 to 100° C. and most preferablyfrom 10 to 40° C., at ambient pressure conditions, i.e. at atmosphericpressure. Alternatively, loading step e2) is carried out in atemperature range from above 0° C., such as in a range from 3 to 180°C., preferably from 10 to 100° C. and most preferably from 10 to 40° C.under vacuum.

In one embodiment, loading step e2) is carried out at ambienttemperature and pressure conditions, e.g., at room temperature, such asfrom about 5 to 35° C., preferably from 10 to 30° C. and most preferablyfrom 15 to 25° C., and at atmospheric pressure. Alternatively, loadingstep e2) is carried out at ambient temperature, e.g., at roomtemperature, such as from about 5 to 35° C., preferably from 10 to 30°C. and most preferably from 15 to 25° C., and under vacuum.

If the method comprises the provision of at least one active ingredientand/or inactive precursor thereof, the method for producing a dosageform comprises, preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules; and    -   e2) loading the compacted form obtained in step b) or the        granules obtained in step c), preferably the granules obtained        in step c), with at least one active ingredient and/or inactive        precursor thereof for obtaining loaded granules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

In one embodiment, the method comprises a step of sieving the granulesobtained in step c) such as to obtain granules of a specific grain size.

If the method further comprises a sieving, the method for producing adosage form comprises, preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules; and    -   e2) loading the compacted form obtained in step b) or the        granules obtained in step c), preferably the granules obtained        in step c), with at least one active ingredient and/or inactive        precursor thereof for obtaining loaded granules;    -   d) sieving of the granules of step c) or e2) by at least one        mesh size;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

It is preferred that the loading step e2) is carried out after sievingstep d). Thus, the method for producing a dosage form comprises,preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step c) by at least one mesh size;        and    -   e2) loading the granules obtained in step d) with at least one        active ingredient and/or inactive precursor thereof for        obtaining loaded granules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

In one embodiment, the method comprises the provision of at least oneactive ingredient and/or inactive precursor thereof and the provision ofat least one formulating aid. Thus, the method for producing a dosageform comprises, preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   e1) mixing the granules obtained in step c) with at least one        formulating aid; and    -   e2) loading the compacted form obtained in step b) or the        granules obtained in step c), preferably the granules obtained        in step c), with at least one active ingredient and/or inactive        precursor thereof for obtaining loaded granules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

If the method further comprises a sieving, the method for producing adosage form comprises, preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step c) or e2) by at least one        mesh size;    -   e1) mixing the granules obtained in step d) with at least one        formulating aid; and    -   e2) loading the compacted form obtained in step b) or the        granules obtained in step c) or step d), preferably the granules        obtained in step d), with at least one active ingredient and/or        inactive precursor thereof for obtaining loaded granules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

Preferably, the loading step e2) is carried out after the sieving stepd). In this embodiment, the method for producing a dosage formcomprises, preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step c) by at least one mesh size;    -   e1) mixing the granules obtained in step d) with at least one        formulating aid; and    -   e2) loading the granules obtained in step d) with at least one        active ingredient and/or inactive precursor thereof for        obtaining loaded granules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

If the method comprises method step e1) and step e2), these steps can becarried out simultaneously or separately in any order.

In one embodiment, method step e1) and step e2) are carried outsimultaneously. For example, method step e1) and step e2) are carriedout simultaneously in that the at least one formulating aid and the atleast one active ingredient and/or inactive precursor thereof areprovided in a blend. That is to say, said at least one formulating aidand the at least one active ingredient and/or inactive precursor thereofmay be pre-mixed prior method step e1) and step e2) are carried out.

In one embodiment, method step e1) and step e2) are carried outindependently from each other, i.e. separately in any order. Forexample, method step e2) is carried out before step e1).

It is appreciated that the granules obtained in step e2) can besubjected to a coating step e3), i.e. before optional tableting step f)is carried out. Such coatings are well known in the art and can beprepared with any conventional coating means known to the skilledperson. Preferably, the coating step is carried out with the at leastone formulating aid defined for mixing step e1).

In a further optional embodiment, the method further comprises a finalstep f) of tableting the granules obtained in step e2) or step e1) orstep d), provided that step d) is carried out after step e2) or stepe1), or filling the granules obtained in step e2) or step e1) or stepd), provided that step d) is carried out after step e2) or step e1),into capsules.

The term “tableting” in the meaning of the present invention refers to aprocess of compacting or moulding a material into the shape of a tablet.The tablet may be in any shape and size known in the art. The “capsules”may be any kind of capsule known in the art. For example, the capsulescan be gelatine or HPMC capsules.

The step f) is carried out at a compressive force in the range from 0.5to 100 kN. It is to be noted that the compressive force used in step f)depends on the specific at least one active ingredient and/or inactiveprecursor thereof provided in step e2). The skilled person will thusadapt the compressive force accordingly. Preferably, the step f) iscarried out at a compressive force in the range from 1.0 to 100 kN, andmost preferably in the range from 1.5 to 80 kN. For example, step f) iscarried out at a compressive force in the range from 2.0 to 60 kN, andmost preferably in the range from 2.5 to 50 kN or from 2.5 to 20 kN.

Tableting can be carried out with any conventional compactor known tothe skilled person. For example, tableting is carried out with a tabletpress such as a Fette 1200i tablet press from Fette Compacting GmbH,Germany.

It is appreciated that the tablets obtained in tableting step f) can besubjected to a final coating step. Such coatings are well known in theart and can be prepared with any conventional coating means known to theskilled person.

In this embodiment, the method for producing a dosage form comprises,preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   e1) optionally mixing the granules obtained in step e2) with at        least one formulating aid;    -   e2) loading the compacted form obtained in step b) or the        granules obtained in step c), preferably the granules obtained        in step c), with at least one active ingredient and/or inactive        precursor thereof for obtaining loaded granules; and    -   f) tableting the granules obtained in step e1) or filling the        granules obtained in step e1) into capsules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

If the method further comprises a sieving, the method for producing adosage form comprises, preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step e2) or, if present, e1) by at        least one mesh size;    -   e1) optionally mixing the granules obtained in step e2) with at        least one formulating aid;    -   e2) loading the compacted form obtained in step b) or the        granules obtained in step c), preferably the granules obtained        in step c), with at least one active ingredient and/or inactive        precursor thereof for obtaining loaded granules;    -   f) tableting the granules obtained in step d) or filling the        granules obtained in step d) into capsules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

Preferably, the loading step e2) is carried out after the sieving stepd). In this embodiment, the method for producing a dosage formcomprises, preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step c) by at least one mesh size;    -   e1) optionally mixing the granules obtained in step e2) with at        least one formulating aid;    -   e2) loading the granules obtained in step d) with at least one        active ingredient and/or inactive precursor thereof for        obtaining loaded granules; and    -   f) tableting the granules obtained in step e2) or, if present,        step e1) or filling the granules obtained in step e2) or, if        present, step e1) into capsules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

Preferably, the method for producing a dosage form comprises, preferablyconsists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step c) by at least one mesh size;    -   e1) mixing the granules obtained in step e2) with at least one        formulating aid;    -   e2) loading the granules obtained in step d) with at least one        active ingredient and/or inactive precursor thereof for        obtaining loaded granules; and    -   f) tableting the granules obtained in step e1) or filling the        granules obtained in step e1) into capsules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

Alternatively, the method for producing a dosage form comprises,preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step c) by at least one mesh size;    -   e1) mixing the granules obtained in step d) with at least one        formulating aid;    -   e2) loading the granules obtained in step e1) with at least one        active ingredient and/or inactive precursor thereof for        obtaining loaded granules; and    -   f) tableting the granules obtained in step e2) or filling the        granules obtained in step e2) into capsules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

In one embodiment, the method for producing a dosage form comprises,preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step c) by at least one mesh size;    -   e1) mixing the granules obtained in step d) with at least one        formulating aid;    -   e2) loading the granules obtained in step e1) with at least one        active ingredient and/or inactive precursor thereof for        obtaining loaded granules;    -   e3) coating the granules obtained in step e2) with at least one        formulating aid;    -   f) tableting the granules obtained in step e3) or filling the        granules obtained in step e3) into capsules; and        wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

Alternatively, the method for producing a dosage form comprises,preferably consists of, the steps of:

-   -   a) providing a surface-reacted calcium carbonate, wherein the        surface-reacted calcium carbonate is a reaction product of        natural ground or precipitated calcium carbonate with carbon        dioxide and one or more H₃O⁺ ion donors in an aqueous medium,        wherein the carbon dioxide is formed in-situ by the H₃O⁺ ion        donor treatment and/or is supplied from an external source;    -   b) compacting the surface-reacted calcium carbonate of step a)        by means of a roller compacter at a compaction pressure in the        range from 1 to 30 kN/cm into a compacted form;    -   c) milling the compacted form of step b) into granules;    -   d) sieving of the granules of step c) by at least one mesh size;    -   e1) mixing the granules obtained in step e2) with at least one        formulating aid;    -   e2) loading the granules obtained in step d) with at least one        active ingredient and/or inactive precursor thereof for        obtaining loaded granules;    -   e3) coating the granules obtained in step e1) with at least one        formulating aid; and    -   f) tableting the granules obtained in step e3) or filling the        granules obtained in step e3) into capsules;    -   wherein the compacted form obtained in step b) consists of the        surface-reacted calcium carbonate of step a).

The dosage form obtained by the method may be a granule, tablet,mini-tablet or capsule.

Thus, in one aspect, the present invention further refers to granulesconsisting of the surface reacted calcium carbonate as defined hereinand optionally mixed with at least one formulating aid as defined hereinand/or loaded with at least one active ingredient and/or inactiveprecursor thereof as defined herein. For example, the granules consistof the surface reacted calcium carbonate as defined herein and mixedand/or coated with at least one formulating aid as defined herein and/orloaded with at least one active ingredient and/or inactive precursorthereof as defined herein. Preferably, the granules consist of thesurface reacted calcium carbonate as defined herein and mixed with atleast one formulating aid as defined herein or loaded with at least oneactive ingredient and/or inactive precursor thereof as defined herein,preferably loaded with at least one active ingredient and/or inactiveprecursor thereof as defined herein. Alternatively, the granules consistof the surface reacted calcium carbonate as defined herein and mixedwith at least one formulating aid as defined herein and loaded with atleast one active ingredient and/or inactive precursor thereof as definedherein. Preferably, the granules are obtained by the method as definedherein.

In another aspect, the present invention further refers to tabletsand/or capsules obtained by the method as defined herein.

The dosage form thus may be prepared in a wide size range, whereindifferent size fractions may be separated by conventional means such assieving.

Generally, the dosage form may have a weight median particle size offrom 0.1 to 20.0 mm, preferably 0.2 to 15.0 mm and more preferably from0.3 to 10.0 mm.

In view of the good results obtained the present invention refers inanother aspect to the dosage form, preferably a tablet, mini-tablet orcapsule, obtained by the method.

Another aspect refers to the use of the granules as defined herein, orthe tablets and/or capsules as defined herein, or the dosage form asdefined herein in a pharmaceutical, nutraceutical, agricultural,cosmetic, home, packaging food, and personal care product.

According to a further aspect, a pharmaceutical, nutraceutical,agricultural, cosmetic, home, food, packaging and personal care productcomprising the granules as defined herein, or the tablets and/orcapsules as defined herein, or the dosage form as defined herein, isprovided.

A further aspect refers to the use of a surface-reacted calciumcarbonate in a method as defined herein.

With regard to the definition of the method, the dosage form, thesurface-reacted calcium carbonate, the at least one active ingredientand/or inactive precursor thereof, the at least one formulating aid andpreferred embodiments thereof, reference is made to the statementsprovided above when discussing the technical details of the method ofthe present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a SEM picture of FCC consisting granules.

FIG. 2 shows a SEM picture of FCC consisting granules loaded with 10%eugenol.

FIG. 3 shows a SEM picture of FCC consisting granules loaded with 25%eugenol.

FIG. 4 shows a SEM picture of FCC consisting granules loaded with 40%eugenol.

FIG. 5 shows a SEM picture of FCC consisting granules loaded with 10%ibuprofen.

FIG. 6 shows a SEM picture of FCC consisting granules loaded with 40%ibuprofen.

The following examples and tests will illustrate the present invention,but are not intended to limit the invention in any way.

EXAMPLES Materials and Methods 1. Measurement Methods

The following measurement methods were used to evaluate the parametersgiven in the examples and claims.

BET Specific Surface Area (SSA) of a Material

The BET specific surface area was measured via the BET process accordingto ISO 9277 using nitrogen, following conditioning of the sample byheating at 250° C. for a period of 30 minutes. Prior to suchmeasurements, the sample was filtered, rinsed and dried at 110° C. in anoven for at least 12 hours.

Particle Size Distribution (Volume % Particles with a Diameter <X), d₅₀Value (Volume Median Grain Diameter) and d₉₈ Value of a ParticulateMaterial:

Volume median grain diameter d₅₀ was evaluated using a MalvernMastersizer 2000 Laser Diffraction System. The d₅₀ or d₉₈ value,measured using a Malvern Mastersizer 2000 Laser Diffraction System,indicates a diameter value such that 50% or 98% by volume, respectively,of the particles have a diameter of less than this value. The raw dataobtained by the measurement is analysed using the Mie theory, with aparticle refractive index of 1.57 and an absorption index of 0.005.

The weight median grain diameter is determined by the sedimentationmethod, which is an analysis of sedimentation behaviour in a gravimetricfield. The measurement is made with a Sedigraph™ 5100 of MicromeriticsInstrument Corporation. The method and the instrument are known to theskilled person and are commonly used to determine grain size of fillersand pigments. The measurement is carried out in an aqueous solution of0.1 wt.-% Na₄P₂O₇. The samples were dispersed using a high speed stirrerand sonicated.

A vibrating sieve tower was used to analyze the particle sizedistribution of the granules. Aliquots of 120 g of granules were put onsteel wire screens (Retsch, Germany) with mesh sizes of 90 μm, 180 μm,250 μm, 355 μm, 500 μm, 710 μm and 1 mm. The sieving tower was shakenfor 3 minutes with 10 seconds interval at a shaking displacement of 1mm.

The processes and instruments are known to the skilled person and arecommonly used to determine grain size of fillers and pigments.

Intra-Particle Intruded Specific Pore Volume (in Cm³/g) of SurfaceReacted Calcium Carbonate

The specific pore volume is measured using a mercury intrusionporosimetry measurement using a Micromeritics Autopore V 9620 mercuryporosimeter having a maximum applied pressure of mercury 414 MPa (60 000psi), equivalent to a Laplace throat diameter of 0.004 μm (˜nm). Theequilibration time used at each pressure step is 20 seconds. The samplematerial is sealed in a 5 cm³ chamber powder penetrometer for analysis.The data are corrected for mercury compression, penetrometer expansionand sample material compression using the software Pore-Comp (Gane, P.A. C., Kettle, J. P., Matthews, G. P. and Ridgway, C. J., “Void SpaceStructure of Compressible Polymer Spheres and Consolidated CalciumCarbonate Paper-Coating Formulations”, Industrial and EngineeringChemistry Research, 35(5), 1996, p 1753-1764.).

The total pore volume seen in the cumulative intrusion data can beseparated into two regions with the intrusion data from 214 μm down toabout 1-4 μm showing the coarse packing of the sample between anyagglomerate structures contributing strongly. Below these diameters liesthe fine inter-particle packing of the particles themselves. If theyalso have intra-particle pores, then this region appears bi modal, andby taking the specific pore volume intruded by mercury into pores finerthan the modal turning point, i.e. finer than the bi-modal point ofinflection, we thus define the specific intra-particle pore volume. Thesum of these three regions gives the total overall pore volume of thepowder, but depends strongly on the original sample compaction/settlingof the powder at the coarse pore end of the distribution.

By taking the first derivative of the cumulative intrusion curve thepore size distributions based on equivalent Laplace diameter, inevitablyincluding pore-shielding, are revealed. The differential curves clearlyshow the coarse agglomerate pore structure region, the inter-particlepore region and the intra-particle pore region, if present. Knowing theintra-particle pore diameter range it is possible to subtract theremainder inter-particle and inter-agglomerate pore volume from thetotal pore volume to deliver the desired pore volume of the internalpores alone in terms of the pore volume per unit mass (specific porevolume). The same principle of subtraction, of course, applies forisolating any of the other pore size regions of interest.

Intra-Particle Intruded Specific Pore Volume (in Cm³/g) of SurfaceReacted Calcium Carbonate Granules Loaded with Active

The specific pore volume is measured using a mercury intrusionporosimetry measurement using a Micromeritics Autopore V 9620 mercuryporosimeter having a maximum applied pressure of mercury 414 MPa (60 000psi), equivalent to a Laplace throat diameter of 0.004 μm (˜nm). Theequilibration time used at each pressure step is 20 seconds. The samplematerial is sealed in a 3 cm3 chamber powder penetrometer for analysis.The data are corrected for mercury compression, penetrometer expansionand sample material compression using the software Pore-Comp (Gane, P.A. C., Kettle, J. P., Matthews, G. P. and Ridgway, C. J., “Void SpaceStructure of Compressible Polymer Spheres and Consolidated CalciumCarbonate Paper-Coating Formulations”, Industrial and EngineeringChemistry Research, 35(5), 1996, p 1753-1764).

The first derivative of the cumulative intrusion curve showed the intraand inter-particle pore volume regions are not independent and separablein all cases. Thus, in order to show the pore volume difference for theloaded samples compared to the empty granules, the pore volume for eachsample was obtained by taking the cumulative intrusion curve for porediameters below 5 μm, representing the intrusion volume from the sum ofthe intra and inter particle pore volumes of the granulated materials.

Loose Bulk Density

120 g of the granules of selected granular fraction (from 180 μm to 710μm) were sieved through a 0.5 mm screen by means of a brush. 100±0.5 gof this sample were carefully filled through a powder funnel into the250 mL measuring cylinder and the volume was read off to the nearest 1mL. The loose bulk density was the calculated according the formula:

Loose bulk density [g/mL]=bulk volume [mL]/weighed sample [g]

and the result was recorded to the nearest 0.01 g/mL.

Tapped Density

120 g of the granules of selected granular fraction (from 180 μm to 710μm) were sieved through a 0.5 mm screen by means of a brush. 100±0.5 gof this sample were carefully filled through a powder funnel into the250 mL measuring cylinder. The graduated cylinder is connected to asupport provided with a settling apparatus capable of producing taps.The cylinder is secured in this support and the volume after 1250 tapsis read. A subsequent second tapping step consisting of 1250 taps isperformed and the value of the volume is read. When this second tappedvolume value does not differ in more than 2 mL from this first tappedvolume value, this is the tapped volume. When this value differs in morethan 2 mL, the tapping step of 1250 taps is repeated until nodifferences of more than 2 mL in subsequent steps is observed.

Angle of Repose

The angle of repose is measured in a flowability tester. The hopperequipped with the 10 mm nozzle is filled with approximately 150 ml ofgranulate. After emptying the hopper, the granulate bevel is measured bymeans of a laser beam and the angle of repose is calculated. The angleof repose B is the angle of the bevel flank opposite the horizontal linethat is calculated as shown in FIG. 7.

Compressibility Index

The compressibility index is calculated as follows:

Compressibility Index=(Tapped density−Bulk density)/Tapped density*100

Thermo Gravimetric Analysis (TGA)

The TGA is basically used to determine the loss ignition of mineralsamples and filled organic materials. The equipment used to measure theTGA was the Mettler-Toledo TGA/DSC1 (TGA 1 STARe System) and thecrucibles used were aluminium oxide 900 μl. The method consists of twoheating steps the first between 30-130° C. for 10 minutes at a heatingrate of 20° C./minute and the second one between 130-570° C. for 20minutes at a heating rate of 20° C./minute.

2. Material

Surface-reacted calcium carbonate (FCC), (from Omya International AG,Switzerland) was compared to microcrystalline cellulose (Avicel® PH 102,FMC BioPolymer, Ireland). Further details of the surface-reacted calciumcarbonate are summarized in the following table 1:

TABLE 1 Intra- Mean particle weight BET Stratum/ intruded Apparentmedian Top cut Specific and specific true particle particle surface Coreinterparticle pore density size size d₉₈ area voids voids volume [g/cm³][μm] [μm] [m²/g] [%, v/v] [%, v/v] [cm³/g] 2.7259 6.15 15 55.52 11 890.97

Eugenol (≥98%, FCC, FG, Sigma Aldrich, W246700, CAS No. 97-53-0,

EC No. 202-589-1) and ibuprofen (Shashun Pharmaceuticals Limited,BP/Ph.Eur., Cas#15687-27-1) were chosen as active ingredients.

3. Granulation Experiments Granulation of FCC by Roller Compaction

The granulation was performed using the Fitzpatrick CCS220. A bar milland a rasped 1 mm screen were used for granulation. The parameters setwere:

Roll gap 0.7 mm (actual value during process 0.9 rpm) Roll force 5 kN/cmRoll speed 8 rpm Horizontal screw 25 rpm (actual value during process 13rpm) speed Vertical screw speed 250 rpm Mill speed 500 rpm

The granule fraction between 250-710 μm was produced using a Retschtower sieve shaker AS300 with 90, 180, 250, 355, 500, 710 and 1000 μm.

The particle size distribution and further parameters are outlined intables 2, 3 and 4.

TABLE 2 Particle size distribution of manufactured empty granules MeanPSD Granules manufactured with Granule size FCC (Mass fraction %) range(μm) 0.01  0-90 3.32  90-180 18.37 180-250 17.90 250-355 18.34 355-50036.18 500-710 5.85   710-1 000 0.01 <1 000

TABLE 3 Parameters measured in the 250-710 μm range Parameters Emptygranules Specific surface area 52 (m²/g) Particle median diameter 500(sieve) (d₅₀, μm) Bulk density (g/mL) 0.48 Tapped density (g/mL) 0.61Compressibility Index 21.31 Angle of repose (°) 47

TABLE 4 Pore Volume Parameters Empty granules Truncated volume cm³/g -0.897 diameter range 0.004-4.9 μmTableting with Granules Obtained from FCC Granules Loaded with Eugenol

The granules obtained from eugenol loaded FCC were further mixed with0.5 wt.-% lubricant (Magnesium stearate, Ligamed MF-2-V, Cas#557-04-0,Peter Greven) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 5minutes. The mix was further used to prepare tablets in a Fette 1200iusing EU1″ tooling, a 10 mm fill cam, 8 standard convex round 10 mmpunches and a tableting speed of 15000 tablets/hour. The fill depth wasadjusted to obtain compression forces of 2, 4 and 6 kN and the tableweight was fixed at 175 mg. The tableting parameters are outlined intable 5.

TABLE 5 Tableting parameters Tablet hardness empty granules Parameters(N) Compression 2 35 force (kN) 4 83 6 119

A SEM picture of FCC consisting granules is shown in FIG. 1.

Loading FCC Granules with Eugenol

150 g of FCC granules (250-710 μm) were placed on a 3 L plastic beaker.The granules were loaded with 16.7 g (10 wt.-%), 50 g (25 wt.-%) and 100g of eugenol (40 wt.-%) of Eugenol (Sigma Aldrich W246700). The eugenolwas loaded by dropping at a rate of 1-2 drops/second by means of aperistaltic pump Ismatec IPC 8 with a two-stop tubing 1.52 mm wide.While loading, the granules were permanently mixed with an overheadstirrer IKA RW20 at a speed ranging between 80 and 120 rpm using an openblade paddle mixer. After the total amount of liquid was loaded onto theFCC granules the loaded granules were left to mix 10 minutes longer.

The results obtained from eugenol loaded FCC granules are outlined intables 6, 7 and 8.

TABLE 6 Particle size distribution of manufactured granules FCC granulesFCC granules loaded with loaded with FCC granules 40 wt.-% 10 wt.-%loaded with eugenol eugenol. 25 wt.-% eugenol Mass fraction Granule sizeMass fraction (%) Mass fraction (%) (%) range (μm) 0.13 1.06 0.13  0-903.56 4.18 1.82  90-180 7.49 5.31 3.47 180-250 14.41 11.41 9.11 250-35526.35 25.40 21.30 355-500 47.43 50.27 44.52 500-710 0.57 1.86 14.23  710-1 000 0.06 0.53 5.42 >1 000

TABLE 7 Parameters measured in the 250-710 μm range FCC granules FCCgranules FCC granules loaded with loaded with loaded with 40 wt.-%Parameters 10 wt.-% eugenol 25 wt.-% eugenol eugenol Particle median 499510 568 diameter (sieve) (d₅₀, μm) Bulk density 0.56 0.69 1.1 (g/mL)Tapped density 0.67 0.76 0.93 (g/mL) Compressibility 16.42 9.21 15.45Index Angle of repose (°) 50 45 64 Loading % (TGA) 8.21 23.80 39.53

TABLE 8 Pore Volume Tablet hardness Tablet hardness Tablet hardnessgranules granules FCC granules manufactured manufactured loaded withwith 25 wt.-% with 40 wt.-% 10 wt.-% eugenol. eugenol loaded eugenolloaded Parameters (N) FCC (N) FCC (N) Truncated volume 0.701 0.409 0.105cm³/g - diameter range 0.004-4.9 μmTableting with Granules Obtained from FCC Granules Loaded with Eugenol

The granules obtained from eugenol loaded FCC were further mixed with0.5 wt.-% lubricant (Magnesium stearate, Ligamed MF-2-V, Cas#557-04-0,Peter Greven) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 5minutes. The mix was further used to prepare tablets in a Fette 1200iusing EU1″ tooling, a 10 mm fill cam, 8 standard convex round 10 mmpunches and a tableting speed of 15 000 tablets/hour. The fill depth wasadjusted to obtain compression forces of 2, 4 and 6 kN and the tableweight was fixed at 175 mg. The tableting parameters are outlined intable 9.

TABLE 9 Tableting parameters Tablet hardness FCC granules Tablethardness Tablet hardness loaded FCC granules FCC granules with loadedwith loaded with 40 wt.-% 10 wt.-% 25 wt.-% eugenol. Parameters eugenol.(N) eugenol. (N) (N) Compression 2 33 20 N/A force (kN) 4 59 20 N/A 6 8516 N/A

SEM pictures of granules loaded with 10% or 25% or 40% eugenol are shownin FIGS. 2, 3 and 4.

Loading FCC Granules with Ibuprofen

150 g of FCC granules (250-710 μm) were placed on a 3 L plastic beaker.The powder was loaded with 16.7 g (10 wt.-%) and 100 g (40% w/w) ofIbuprofen (BASF). The ibuprofen was first dissolved in acetone 75 g and150 g for the 10 wt.-% and 40 wt.-% loadings, respectively. Theibuprofen acetone solution was loaded by spraying at a rate of 5 hitsevery 15 seconds by means of a spray bottle. While loading, the granuleswere permanently mixed with an overhead stirrer IKA RW20 at a speedranging between 80 and 120 rpm using an open blade paddle mixer. Afterthe total amount of solution was loaded onto the FCC granules the loadedgranules were left to mix 10 minutes longer. The loaded granules weredried at a vacuum oven ThermoScientific VT 6130 until no more solventcould be collected.

The results obtained from ibuprofen loaded FCC granules are outlined intables 10, 11 and 12.

TABLE 10 Particle size distribution of manufactured granules FCCgranules FCC granules loaded with loaded with Granule size range 10wt.-% Ibuprofen 40 wt.-% Ibuprofen (μm) 0.74 1.33  0-90 2.54 2.51 90-180 5.02 3.93 180-250 11.44 10.23 250-355 25.75 20.01 355-500 50.3043.46 500-710 3.75 14.45   710-1 000 0.47 4.08 >1 000

TABLE 11 Parameters measured in the 250-710 μm range FCC granules FCCgranules loaded with loaded with Parameters 10 wt.-% Ibuprofen 40 wt.-%Ibuprofen Particle median 520 555 diameter (sieve) (d₅₀, μm) Bulkdensity (g/mL) 0.65 0.65 Tapped density 0.65 0.69 (g/mL) Compressibility0 5.80 Index Angle of repose (°) 36.20 36.40 Loading % (TGA) 7.39 33.63

TABLE 12 Pore Volume Tablet hardness Tablet hardness FCC granules FCCgranules loaded with loaded with 10 wt.-% 40 wt.-% Parameters Ibuprofen(N) Ibuprofen (N) Truncated volume 0.629 0.420 cm³/g - diameter range0.004-4.9 μmTableting with Granules Obtained from FCC Granules Loaded with Ibuprofen

The granules obtained from eugenol loaded FCC were further mixed with0.5 wt.-% lubricant (Magnesium stearate, Ligamed MF-2-V, Cas#557-04-0,Peter Greven) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 5minutes. The mix was further used to prepare tablets in a Fette 1200iusing EU1″ tooling, a 10 mm fill cam, 8 standard convex round 10 mmpunches and a tableting speed of 15 000 tablets/hour. The fill depth wasadjusted to obtain compression forces of 2, 4 and 6 kN and the tableweight was fixed at 175 mg. The tableting parameters are outlined intable 13.

TABLE 13 Tableting parameters Tablet hardness Tablet hardness FCCgranules FCC granules loaded with loaded with 10 wt.-% 40 wt.-%Parameters Ibuprofen (N) Ibuprofen (N) Compression 2 21 36 force (kN) 445 67 6 67 64

SEM pictures of granules loaded with 10% or 40% ibuprofen are shown inFIGS. 5 and 6.

1. A method of producing granules comprising surface-reacted calciumcarbonate, the method comprising the steps of: a) providing thesurface-reacted calcium carbonate, wherein the surface-reacted calciumcarbonate is a reaction product of natural ground or precipitatedcalcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors inan aqueous medium, wherein the carbon dioxide is formed in-situ by theH₃O⁺ ion donor treatment and/or is supplied from an external source; b)compacting the surface-reacted calcium carbonate of step a) by means ofa roller compacter at a compaction pressure in the range from 1 kN/cm to30 kN/cm into a compacted form; c) milling the compacted form of step b)into granules; wherein the compacted form obtained in step b) comprisesthe surface-reacted calcium carbonate of step a).
 2. The methodaccording to claim 1, wherein the natural ground calcium carbonatecomprises a calcium carbonate containing mineral selected from the groupconsisting of marble, chalk, dolomite, limestone and mixtures thereof;or the precipitated calcium carbonate comprises a precipitated calciumcarbonate having aragonitic, vateritic or calcitic mineralogical crystalforms and mixtures thereof.
 3. The method according to claim 1, whereinthe surface-reacted calcium carbonate a) has a BET specific surface areaof from 20 m²/g to 450 m²/g measured using the nitrogen and BET methodaccording to ISO 9277; and/or b) comprises particles having a volumemedian grain diameter d₅₀ of from 1 μm to 50 μm; and/or c) has anintra-particle intruded specific pore volume within the range of 0.15cm³/e to 1.35 cm³/g calculated from a mercury intrusion porosimetrymeasurement.
 4. The method according to claim 1, wherein rollercompacting step b) is carried out at a roller compaction pressure in therange from 1 kN/cm to 28 kN/cm.
 5. The method according to claim 1,further comprising a step d) of sieving the granules of step c) by atleast one mesh size.
 6. The method according to claim 5, wherein sievingstep d) is carried out by sieving on two or more different mesh sizesselected from the group consisting of 90 μm, 180 μm, 250 μm, 355 μm, 500μm and 710 μm.
 7. The method according to claim 1, further comprising astep e1) of mixing the granules obtained in step c) and/or, if present,step d) with at least one formulating aid.
 8. The method according toclaim 7, wherein the at least one formulating aid is selected from thegroup consisting of a disintegrant, a lubricant, an impact modifier, aplasticizer, a wax, a stabilizer, a pigment, a coloring agent, ascenting agent, a taste masking agent, a flavoring agent, a sweetener, amouth-feel improver, a diluent, a film forming agent, an adhesive, abuffer, a adsorbent, an odor-masking agent and mixtures thereof.
 9. Themethod according to claim 1, further comprising a step e2) of loadingthe compacted form obtained in step b) or the granules obtained in stepc) or, if present, step d) with at least one active ingredient and/orinactive precursor thereof for obtaining loaded granules.
 10. The methodaccording to claim 9, wherein the at least one active ingredient and/orinactive precursor thereof is selected from the group consisting offragrances, flavours, herbal extracts, fruit extracts, nutrients, traceminerals, repellents, food, cosmetics, flame retardants, enzymes,macromolecules, pesticides, fertilizers, preserving agents,antioxidants, reactive chemicals, pharmaceutically active agents orpharmaceutically inactive precursors of synthetic origin, semi-syntheticorigin, natural origin thereof, and mixtures thereof.
 11. The methodaccording to claim 9, wherein the at least one active ingredient and/orinactive precursor thereof is in liquid form.
 12. The method accordingto claim 9, wherein loading step e2) is carried out by spraying ordropping the at least one active ingredient and/or inactive precursorthereof onto the compacted form obtained in step b) or the granulesobtained in step c) or, if present, step d) and mixing in a deviceselected from the group consisting of a fluidized bed dryer/granulator,a ploughshare mixer, a vertical mixer, a horizontal mixer, a high shearmixer, a low shear mixer and a high speed blender.
 13. The methodaccording to claim 9, further comprising a final step f) of tabletingthe loaded granules obtained in step e2) or filling the loaded granulesobtained in step e2) into capsules.
 14. Granules comprising asurface-reacted calcium carbonate as defined in claim 1 and optionallymixed with at least one formulating aid and/or loaded with at least oneactive ingredient and/or inactive precursor thereof.
 15. A tablet and/orcapsule obtained by the method according to claim
 13. 16. A dosage formcomprising the granules of claim
 14. 17. A method of making a product,the method comprising incorporating the granules of claim 14, into theproduct, wherein the product is selected from the group consisting of apharmaceutical product, a nutraceutical product, an agriculturalproduct, a cosmetic product, a home product, a food product, a packagingproduct and a personal care product.
 18. A pharmaceutical product, anutraceutical product, an agricultural product, a cosmetic product, ahome product, a food product, a packaging product and a personal careproduct comprising the granules of claim
 14. 19. (canceled)
 20. Themethod according to claim 11, wherein the at least one active ingredientand/or inactive precursor thereof is provided in a solvent selected fromthe group consisting of water, methanol, ethanol, n-butanol,isopropanol, n-propanol, n-octanol, acetone, dimethylsulphoxide,dimethylformamide, tetrahydrofurane, vegetable oils and derivativesthereof, animal oils and derivatives thereof, molten fats and waxes, andmixtures thereof.
 21. A method of making a product, the methodcomprising incorporating the tablets and/or capsules of claim 15 intothe product, wherein the product is selected from the group consistingof a pharmaceutical product, a nutraceutical product, an agriculturalproduct, a cosmetic product, a home product, a food product, a packagingproduct and a personal care product.
 22. A method of making a product,the method comprising incorporating the dosage form of claim 16, intothe product, wherein the product is selected from the group consistingof a pharmaceutical product, a nutraceutical product, an agriculturalproduct, a cosmetic product, a home product, a food product, a packagingproduct and a personal care product.
 23. A pharmaceutical product, anutraceutical product, an agricultural product, a cosmetic product, ahome product, a food product, a packaging product and a personal careproduct comprising the tablets and/or capsules of claim
 15. 24. Apharmaceutical product, a nutraceutical product, an agriculturalproduct, a cosmetic product, a home product, a food product, a packagingproduct and a personal care product comprising the dosage form of claim16.